Piperidine and piperazine phenyl sulfonamides as modulators of ion channels

ABSTRACT

The present invention relates to piperidine and piperazine phenyl sulfonamides useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including for example the treatment of pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims the benefit under 35 U.S.C. §119 of U.S.provisional application Ser. No. 60/752,926, titled “HETEROCYCLICDERIVATIVES AS MODULATORS OF ION CHANNELS” filed Dec. 21, 2005; U.S.provisional application Ser. No. 60/791,181, titled “HETEROCYCLICDERIVATIVES AS MODULATORS OF ION CHANNELS” filed Apr. 11, 2006; U.S.provisional application Ser. No. 60/799,797, titled “HETEROCYCLICDERIVATIVES AS MODULATORS OF ION CHANNELS” filed May 12, 2006; and U.S.provisional application Ser. No. 60/839,444, titled “HETEROCYCLICDERIVATIVES AS MODULATORS OF ION CHANNELS” filed Aug. 23, 2006, with theentire contents of each application being incorporated herein byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ionchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy andsodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain(See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels andpain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R.Cummins, et al. (2000) “Voltage-gated sodium channels and the molecularpathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28),myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonicdisorders and in muscle channelopathies” Neurol Sci 21 (5): S953-61 andMankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr OpinNeurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, etal. (2002) “Mutations of voltage-gated sodium channels in movementdisorders and epilepsy” Novartis Found Symp 241: 72-81), multiplesclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensoryneuron-specific sodium channel SNS is abnormally expressed in the brainsof mice with experimental allergic encephalomyelitis and humans withmultiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, andRenganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8sodium channels perturbs the firing patterns of cerebellar purkinjecells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E.Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodiumcurrents in colon sensory neurons from rat dorsal root ganglia” Am JPhysiol 277 (6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al.(2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8(SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinenceand visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “Theinvolvement of the tetrodotoxin-resistant sodium channel Na(v)1.8(PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6),as well as an array of psychiatry dysfunctions such as anxiety anddepression (See, Hurley, S. C. (2002) “Lamotrigine update and its use inmood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypesshow tissue specific localization and functional differences (See,Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu RevPhysiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5)are resistant to block by the well-known Na channel blocker TTX,demonstrating subtype specificity within this gene family. Mutationalanalysis has identified glutamate 387 as a critical residue for TTXbinding (See, Noda, M., H. Suzuki, et al. (1989) “A single pointmutation confers tetrodotoxin and saxitoxin insensitivity on the sodiumchannel II” FEBS Lett 259(1): 213-6).

TABLE 1 (Abbreviations: CNS = central nervous system, PNS = peripheralnervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): Naisoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nM Pain,Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10 nMNeurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic,injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart 2 μMArrhythmia, long QT NaV1.6 CNS 6 nM Pain, movement disorders widespread,most abundant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminalsdisorders neuroendocrine NaV1.8 PNS, small >50 μM Pain neurons in DRG &TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See,Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See,Rozen, T. D. (2001) “Antiepileptic drugs in the management of clusterheadache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 andJensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine(See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment ofneuropathic pain” Neurology 59 (5 Suppl 2): S14-7), have been shown tobe useful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter; and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379(6562): 257-62.). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S.Gold, et al. (2002) “Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade ofneuropathic pain by antisense targeting of tetrodotoxin-resistant sodiumchannels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8protein is upregulated along uninjured C-fibers adjacent to the nerveinjury. Antisense treatment prevents the redistribution of NaV1.8 alongthe nerve and reverses neuropathic pain. Taken together thegene-knockout and antisense data support a role for NaV1.8 in thedetection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channeldistribution and subtype. In the injured nerve, expression of NaV1.8 andNaV1.9 are greatly reduced whereas expression of the TTX sensitivesubunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell,et al. (1999) “Plasticity of sodium channel expression in DRG neurons inthe chronic constriction injury model of neuropathic pain.” Pain 83(3):591-600.) The timecourse of the increase in NaV1.3 parallels theappearance of allodynia in animal models subsequent to nerve injury. Thebiophysics of the NaV1.3 channel is distinctive in that it shows veryfast repriming after inactivation following an action potential. Thisallows for sustained rates of high firing as is often seen in theinjured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3sodium channels: rapid repriming and slow closed-state inactivationdisplay quantitative differences after expression in a mammalian cellline and in spinal sensory neurons” J Neurosci 21(16): 5952-61.). NaV1.3is expressed in the central and peripheral systems of man. NaV1.9 issimilar to NaV1.8 as it is selectively localized to small sensoryneurons of the dorsal root ganglion and trigeminal ganglion (See, Fang,X., L. Djouhri, et al. (2002). “The presence and role of thetetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptiveprimary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slowrate of inactivation and left-shifted voltage dependence for activation(See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodiumchannel with unique properties” Trends Neurosci 25(5): 253-9.). Thesetwo biophysical properties allow NaV1.9 to play a role in establishingthe resting membrane potential of nociceptive neurons. The restingmembrane potential of NaV1.9 expressing cells is in the −55 to −50 mVrange compared to −65 mV for most other peripheral and central neurons.This persistent depolarization is in large part due to the sustainedlow-level activation of NaV1.9 channels. This depolarization allows theneurons to more easily reach the threshold for firing action potentialsin response to nociceptive stimuli. Compounds that block the NaV1.9channel may play an important role in establishing the set point fordetection of painful stimuli. In chronic pain states, nerve and nerveending can become swollen and hypersensitive exhibiting high frequencyaction potential firing with mild or even no stimulation. Thesepathologic nerve swellings are termed neuromas and the primary Nachannels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T.,L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channelsin painful human neuroma-evidence from immunocytochemistry” ActaNeurochir (Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 arealso expressed in dorsal root ganglion neurons and contribute to thesmall TTX sensitive component seen in these cells. NaV1.7 in particularmay therefore be a potential pain target in addition to it's role inneuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al.(1995) “Structure and functional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channel family fromhuman neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1mutations cause febrile seizures associated with afebrile partialseizures.” Neurology 57(4): 703-5.) and NaV1.2 (See, Sugawara, T., Y.Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alphaII subunit gene Na(v)1.2 in a patient with febrile and afebrile seizurescauses channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) havebeen linked to epilepsy conditions including febrile seizures. There areover 9 genetic mutations in NaV1.1 associated with febrile seizures(See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations ofvoltage-gated sodium channels in movement disorders and epilepsy”Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiacarrhythmias. A gene defect in NaV1.5 that produces a largernoninactivating component to the current has been linked to long QT inman and the orally available local anesthetic mexilitine has been usedto treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997)“Pharmacological targeting of long QT mutant sodium channels.” J ClinInvest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1):85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathicpain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H.,R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99(7): 1714-20); neuroprotection (See, Taylor, C. P. and L.S. Narasimhan (1997) “Sodium channels and therapy of central nervoussystem diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See,Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations oflocal anaesthetics unveil the potential role of sodium channels inneuropathic pain” Novartis Found Symp 241: 189-201).

Various animal models with clinical significance have been developed forthe study of sodium channel modulators for numerous different painindications. E.g., malignant chronic pain, see, Kohase, H., et al., ActaAnaesthesiol Scand. 2004; 48(3):382-3; femur cancer pain (see, Kohase,H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3); non-malignantchronic bone pain (see, Ciocon, J. O. et al., J Am Geriatr Soc. 1994;42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav BrainRes. 1987; 24(1):11-29); osteoarthritis (see, Guzman, R. E., et al.,Toxicol Pathol. 2003; 31(6):619-24); spinal stenosis (see, Takenobu, Y.et al., J Neurosci Methods. 2001; 104(2):191-8); Neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9; neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9); myofascial painsyndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002;16(1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24(1):37-46);fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995;15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain ResMol Brain Res. 1999; 67(1):87-97); chronic visceral pain, including,abdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000;119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., NeurosciLett. 1998; 246(2):73-6); pancreatic (see, Vera-Portocarrero, L. B., etal., Anesthesiology. 2003; 98(2):474-84); IBS pain (see, Verne, G. N.,et al., Pain. 2003; 105 (1-2):223-30; La J H et al., WorldGastroenterol. 2003; 9(12):2791-5); chronic headache pain (see, Willimas& Stark, Cephalalgia. 2003; 23(10):963-71); migraine (see, Yamamura, H.,et al., J Neurophysiol. 1999; 81(2):479-93); tension headache,including, cluster headaches (see, Costa, A., et al., Cephalalgia. 2000;20(2):85-91); chronic neuropathic pain, including, post-herpeticneuralgia (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim &Chung 1992, Pain 50:355); diabetic neuropathy (see, Beidoun A et al.,Clin J Pain. 2004; 20(3):174-8; Courteix, C., et al., Pain. 1993;53(1):81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, NedTijdschr Geneeskd. 2001; 145(15):731-5; Joseph E K et al., Pain. 2004;107 (1-2):147-58; Oh, S. B., et al., J. Neurosci. 2001; 21(14):5027-35);trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med OralPathol Oral Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp BrainRes. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda,M., et al., Neuron. 1996; 16(5):1049-60); hereditary sensoryneuropathies (see, Lee, M. J., et al., Hum Mol. Genet. 2003;12(15):1917-25); peripheral nerve injury (see, Attal, N., et al.,Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett &Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149;Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas(see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor &Raber, Behav Neural Biol. 1983; 37(2):276-83); ectopic proximal anddistal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27);radiculopathy (see, Devers & Galer, (see, Clin J Pain. 2000;16(3):205-8; Hayashi N et al., Spine. 1998; 23(8):877-85); chemotherapyinduced neuropathic pain (see, Aley, K. O., et al., Neuroscience. 1996;73(1):259-65); radiotherapy-induced neuropathic pain; post-mastectomypain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain(Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cordinjury pain (see, Hains, B. C., et al., Exp Neurol. 2000;164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., etal., Neurosci Lett. 2000; 290(1):79-83); complex regional pain syndrome(see, Wallace, M. S., et al., Anesthesiology. 2000; 92(1):75-83; XantosD et al., J Pain. 2004; 5 (3 Suppl 2):S1); phanton pain (see, Weber, W.E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain.1981; 10(1):67-73); intractable pain (see, Yokoyama, M., et al., Can JAnaesth. 2002; 49(8):810-3); acute pain, acute post-operative pain (see,Koppert, W., et al., Anesth Analg. 2004; 98(4):1050-5; Brennan, T. J.,et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; jointpain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52(11):817-22);mechanical low back pain (see, Kehl, L. J., et al., Pain. 2000;85(3):333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay,M., et al., Can J Anaesth. 2002; 49(2):137-43); acute visceral pain,including, abdominal pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; etc (see, Giambernardino, M. A., etal., Pain. 1995; 61(3):459-69); chest pain, including, cardiac Pain(see, Vergona, R. A., et al., Life Sci. 1984; 35(18):1877-84); pelvicpain, renal colic pain, acute obstetric pain, including, labor pain(see, Segal, S., et al., Anesth Analg. 1998; 87(4):864-9); cesareansection pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, including, endometriosis (see, Cason, A. M., et al.,Horm Behay. 2003; 44(2):123-31); acute herpes zoster pain; sickle cellanemia; acute pancreatitis (see, Toma, H; Gastroenterology. 2000;119(5):1373-81); breakthrough pain; orofacial pain, including, sinusitispain, dental pain (see, Nusstein, J., et al., J Endod. 1998;24(7):487-91; Chidiac, J. J., et al., Eur J Pain. 2002; 6(1):55-67);multiple sclerosis (MS) pain (see, Sakurai & Kanazawa, J Neurol Sci.1999; 162(2):162-8); pain in depression (see, Greene B, Curr Med ResOpin. 2003; 19(4):272-7); leprosy pain; behcet's disease pain; adiposisdolorosa (see, Devillers & Oranje, Clin Exp Dermatol. 1999;24(3):240-1); phlebitic pain; Guillain-Barre pain; painful legs andmoving toes; Haglund syndrome; erythromelalgia pain (see,Legroux-Crespel, E., et al., Ann Dermatol Venereol. 2003;130(4):429-33); Fabry's disease pain (see, Germain, D. P., J Soc Biol.2002; 196(2):183-90); Bladder and urogenital disease, including, urinaryincontinence (see, Berggren, T., et al., J Urol. 1993; 150 (5 Pt1):1540-3); hyperactivity bladder (see, Chuang, Y. C., et al., Urology.2003; 61(3):664-70); painful bladder syndrome (see, Yoshimura, N., etal., J. Neurosci. 2001; 21(21):8690-6); interstitial cyctitis (IC) (see,Giannakopoulos & Campilomatos, Arch Ital Urol Nefrol Androl. 1992;64(4):337-9; Boucher, M., et al., J Urol. 2000; 164(1):203-8); andprostatitis (see, Mayersak, J. S., Int Surg. 1998; 83(4):347-9; Keith,I. M., et al., J Urol. 2001; 166(1):323-8).

Unfortunately, as described above, the efficacy of currently used sodiumchannel blockers for the disease states described above has been to alarge extent limited by a number of side effects. These side effectsinclude various CNS disturbances such as blurred vision, dizziness,nausea, and sedation as well more potentially life threatening cardiacarrhythmias and cardiac failure. Accordingly, there remains a need todevelop additional Na channel antagonists, preferably those with higherpotency and fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels. These compounds have thegeneral formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides compounds of formulaI:

or a pharmaceutically acceptable salt thereof;

wherein:

ring Z is a 5-7 membered partially unsaturated or aromatic ring having1-4 ring heteroatoms selected from O, S, or N, wherein Z is optionallysubstituted with up to q occurrences of R^(Z) substitutents, whereineach R^(Z) is independently selected from R¹, R², R³, R⁴, or R⁵; and qis 0-4;

W and Y₁ each is independently CH or N, provided that at least one of Wand Y₁ is N;

x and y each is independently 0-3; provided that x+y is 2, 3, or 4;

w is 0-4;

v is 0 or 1;

z is 0-4;

V and X each is a bond, O, NR², or C(R²)₂;

Q is a bond or a C1-C6 straight or branched alkylidene chain, wherein upto two non-adjacent methylene units of Q are optionally andindependently replaced by —CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—,—CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—,—NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—, —NR²SO₂NR²—, or aspirocycloalkylene moiety;

R^(Q) is a C1-C6 aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from O, S, N, or NH, or an 8-15 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ring ortricyclic fused or spirocyclic ring system having 0-5 heteroatomsindependently selected from O, S, N, or NH;

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², R³, R⁴, or R⁵;

R¹¹ is R² or Y;

R²² is R¹, R², or R⁴;

wherein ring A is optionally fused to a phenyl ring, wherein said phenylring is optionally substituted with up to 4 substituents independentlyselected from R¹, R², or R⁴;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), ═N—OR⁶, ═N—OR⁷, R⁶ or(CH₂)_(n)—Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or

-   -   two R¹ on adjacent ring atoms, taken together, form        1,2-methylenedioxy or 1,2-ethylenedioxy;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R³ is optionally substituted with up to 3substituents independently selected from R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶C(S)N(R⁶)₂, NR⁶C(S)NR⁵R⁶, NR⁶C(S)N(R⁵)₂,NR⁵C(S)N(R⁶)₂, NR⁵C(S)NR⁵R⁶, NR⁵C(S)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶,NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂,P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂,P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵));

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R⁵ optionally substituted with up to 3 R¹substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR⁷ substituent;

R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R⁷ is optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2;

-   -   Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂,        CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6)        aliphatic, S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂,        NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)₂,        N((C1-C6)aliphatic)R⁸, COOH, C(O)O(—(C1-C6)aliphatic), or        O—(C1-C6)aliphatic; and

R⁸ is CH₃C(O)—, C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable (i.e.,having the requisite valency available for a given substituent) positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups. The term “cycloaliphatic” means a monocyclichydrocarbon, bicyclic, or tricyclic hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic and has a single point of attachment to the rest of themolecule. In some embodiments, “cycloaliphatic” refers to a monocyclicC₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic, that has a single point of attachment to the rest ofthe molecule wherein any individual ring in said bicyclic ring systemhas 3-7 members.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, or “heterocyclic” as used herein meansnon-aromatic, monocyclic, bicyclic, or tricyclic ring systems in whichone or more ring atoms in one or more ring members is an independentlyselected heteroatom. Heterocyclic ring can be saturated or can containone or more unsaturated bonds. In some embodiments, the “heterocycle”,“heterocyclyl”, or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

The term “spirocycloalkylene” refers to a cycloaliphatic ring that hastwo points of attachment from the same carbon atom to the rest of themolecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds of formula (I), wherein one or more hydrogen atoms arereplaced deuterium or tritium, or one or more carbon atoms are replacedby a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.Such compounds are useful, for example, as analytical tools, probes inbiological assays, or sodium channel blockers with improved therapeuticprofile.

In one embodiment, Z is an optionally substituted ring selected from:

In certain embodiments of the compounds of the present invention, Z isselected from:

wherein Z has up to two substituents selected from R¹, R², or R⁵.

In other embodiments, Z is selected from:

Or, Z is formula i-a.

In other embodiments, Z is selected from:

In certain embodiments of the present invention, Z is selected from:

Or, Z is selected from:

Or, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In one embodiment Z is ii-b. Or, Z is iii-a.

In certain embodiments, Z is selected from:

In other embodiments, Z is selected from:

In other embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In certain embodiments, Z is selected from:

In other embodiments, Z is selected from:

In one embodiment, Z is ix-a. Or, Z is ix-c.

In one embodiment, R^(Z) is R¹. Or, R^(Z) is R². In another embodiment,R^(Z) is R⁴.

In one embodiment, q is 0. Or, q is 1-2.

According to one embodiment of formula I, R¹ is oxo. Or R¹ is ═NN(R⁶)₂,═NN(R⁷)₂, or ═NN(R⁶R⁷). According to another embodiment, R¹ is R⁶.

According to one embodiment, R¹ is (CH₂)_(n)—Y. Or, R¹ is Y.

Exemplary Y includes halo, CN, NO₂, CF₃, OCF₃, OH, SH, S(C1-4aliphatic), S(O)(C1-4 aliphatic), SO₂(C1-4 aliphatic), NH₂, NH(C1-4aliphatic), N(C1-4 aliphatic)2, NR(C1-4 aliphatic)R⁸, COOH, COO(C1-4aliphatic) or O(C1-4 aliphatic). Or, two R¹ on adjacent ring atoms,taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy. In anotherembodiment, Y is halo, OH, SH, CN, NO2, CF₃, OCF₃, COOH, or C(O)O(C1-C4alkyl). In another embodiment, R¹ is selected from halo, cyano,trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, orC(O)C₁₋₄ alkyl.

In another embodiment, R¹ is (CH₂)_(n)—Y. In one embodiment, n is 0or 1. Or, n is 2. In one embodiment, Y is halo, CN, NO₂, CF₃, OCF₃, OR⁶,SR⁶, S(O)R⁶, SO₂R⁶, N(R⁶)₂, NR⁶R⁸, or COOR⁶. In another embodiment, Y ishalo, OH, SH, CN, NO₂, CF₃, OCF₃, or C(O)O(C1-C4 alkyl).

In one embodiment, two R¹ on adjacent ring atoms, taken together, form1,2-methylenedioxy or 1,2-ethylenedioxy.

According to another embodiment of formula (I), R² is a straight orbranched (C1-C6) alkyl or (C2-C6)alkenyl or alkynyl, optionallysubstituted with up to two R¹ substitutions.

In one embodiment, R² is H. In another embodiment, R² is C1-C6aliphatic. In another embodiment, R² is a C1-C6 straight or branchedalkyl. In another embodiment, R² is C1-C4 alkyl. In another embodiment,R² is optionally substituted with up to 2 substituents independentlyselected from R¹ or R⁴. Or, R² is optionally substituted with up to 2substituents independently selected from R¹ or R⁵.

In one embodiment, R³ is a C3-C8 cycloaliphatic optionally substitutedwith up to 3 substituents independently selected from R¹, R², R⁴ or R⁵.Exemplary cycloaliphatics include cyclopropyl, cyclopentyl, cyclohexyl,or cycloheptyl. In another embodiment, R³ is a C6-C10 aryl, optionallysubstituted with up to 3 substituents independently selected from R¹,R², R⁴ or R⁵. Exemplary aryl rings include phenyl or naphthyl. Inanother embodiment, R³ is a C3-C8 heterocyclic, optionally substitutedwith up to 3 substituents independently selected from R¹, R², R⁴ or R⁵.Exemplary heterocyclic rings include azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In anotherembodiment, R³ is a C5-C10 heteroaryl ring, optionally substituted withup to 3 substituents independently selected from R¹, R², R⁴ or R⁵.Exemplary heteroaryl rings include pyridyl, pyrazinyl, triazinyl,furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, imidazolyl, triazolyl, thiadiazolyl, pyrimidinyl,quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, quinolinyl,isoquinolinyl, benzofuranyl, benzothiophenyl, indolizinyl, indolyl,isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzothiazolyl,purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinaoxalinyl,naphthyridinyl, or pteridinyl.

In one embodiment, R⁴ is selected from OR⁵ or OR⁶. Or, R⁴ is selectedfrom OC(O)R⁶ or OC(O)R⁵. In another embodiment, R⁴ is selected fromC(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂ or C(O)N(R⁵R⁶).In yet another embodiment, R⁴ is selected from N(R⁶)₂, N(R⁵)₂, orN(R⁵R⁶). Or, R⁴ is selected from NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵,NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂, NR⁵C(O)NR⁵R⁶,or NR⁵C(O)N(R⁵)₂.

In one embodiment, R⁵ is a C3-C8 cycloaliphatic, optionally substitutedwith up to 3 R¹ substituents. Exemplary cycloaliphatics includecyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl. In anotherembodiment, R⁵ is a C6-C10 aryl, optionally substituted with up to 3 R¹substituents. Exemplary aryl rings include phenyl or naphthyl. Inanother embodiment, R⁵ is a C3-C8 heterocyclic, optionally substitutedwith up to 3 R¹ substituents. Exemplary heterocyclic rings includeazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl. In another embodiment, R⁵ is a C5-C10 heteroaryl ring,optionally substituted with up to 3 R¹ substituents. Exemplaryheteroaryl rings include pyridyl, pyrazyl, triazinyl, furanyl, pyrrolyl,thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, imidazolyl,triazolyl, thiadiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl,benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl,benzothiophenyl, indolizinyl, indolyl, isoindolyl, indolinyl, indazolyl,benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinaoxalinyl, naphthyridinyl, or pteridinyl.

In one embodiment, R⁶ is H. In another embodiment, R⁶ is C1-C6aliphatic, preferably, C1-C6 alkyl. Or, R⁶ is C1-C6 aliphatic optionallysubstituted with a R⁷ substituent.

In one embodiment, R⁷ is a C3-C8 cycloaliphatic, optionally substitutedwith up to 2 substituents independently selected from C1-C6 aliphatic or(CH₂)_(m)—Z′ wherein m is 0-2. Exemplary cycloaliphatics includecyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl. In anotherembodiment, R⁷ is a C6-C10 aryl, optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic or (CH₂)_(m)—Z′wherein m is 0-2. Exemplary aryl rings include phenyl or naphthyl. Or,R⁷ is a C3-C8 heterocyclic ring, optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2. Exemplary heterocyclic rings includeazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orthiomorpholinyl. Or, R⁷ is a C5-C10 heteroaryl ring, optionallysubstituted with up to 2 substituents independently selected from C1-C6aliphatic, or (CH₂)_(m)—Z′ wherein m is 0-2. Exemplary heteroaryl ringsinclude pyridyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl,oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, imidazolyl, triazolyl,thiadiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl,benzothiophenyl, indolizinyl, indolyl, isoindolyl, indolinyl, indazolyl,benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinaoxalinyl, naphthyridinyl, or pteridinyl.

In one embodiment, Z′ is selected from halo, CN, NO₂, C(halo)₃,CH(halo)₂, CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH,S—(C1-C6) aliphatic, S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂,NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)₂, COOH,C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic.

In one embodiment, X is a bond.

In another embodiment, X is O. Or, X is C(R²)₂. Or, X is NR².

In one embodiment, X is CH₂. Or, X is CHMe. Or, X is C(Me)₂.

In another embodiment, X is NMe.

In one embodiment, Q is a bond.

In another embodiment, Q is O, S, or NR². In embodiment, Q is O. Or, Qis S. Or, Q is NR². Or, Q is NH or N(C1-C6) alkyl.

In another embodiment, Q is a C1-C6 straight or branched alkylidinechain, wherein up to one methylene unit of Q is replaced by O, S, NH, orN(C1-C4 alkyl).

In another embodiment, Q is a C1-C6 alkyl, wherein one methylene groupis replaced by a spirocycloalkylene group such as spirocyclopropylene.

In another embodiment, Q is —X₂—(X₁)_(p)—, wherein:

X₂ is C1-C6 aliphatic, optionally substituted with up to twosubstituents independently selected from R¹, R⁴, or R⁵; and

p is 0 or 1; and

X₁ is O, S, or NR².

In one embodiment, X₂ is C1-C6 alkyl or C2-C6 alkylidene. Or, X₂ isC1-C6 alkyl optionally substituted with R¹ or R⁴. In one embodiment, X₂is selected from —CH₂—, —CH₂—CH₂—, —(CH₂)₃—, —C(Me)₂-, —CH(Me)—,—C(Me)=CH—, —CH═CH—, —CH(Ph)—, —CH₂—CH(Me)—, —CH(Et)-, or —CH(i-Pr)—.

In certain embodiments, X₁ is NH. Or, X₁ is —N(C1-C4 alkyl)-.

In one embodiment, p is O.

In another embodiment, p is 1 and X₁ is O.

In another embodiment, p is 1, and X₁ is S.

In another embodiment, p is 1, and X₁ is NR². Preferably, R² ishydrogen.

In one embodiment, z is 0. Or, z is 1. In another embodiment, z is 2.

In one embodiment, R^(Q) is a C1_C6 aliphatic group, wherein R^(Q) isoptionally substituted with up to 4 substituents independently selectedfrom R¹, R², R³, R⁴, or R⁵.

In another embodiment, R^(Q) is a 3-8-membered saturated, partiallyunsaturated, or aromatic monocyclic ring having 0-3 heteroatomsindependently selected from O, S, N, or NH, wherein R^(Q) is optionallysubstituted with up to 4 substituents selected from R¹, R², R³, R⁴, orR⁵. In one embodiment, R^(Q) is optionally substituted with up to 3substituents selected from halo, cyano, trifluoromethyl, OH, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

In one embodiment, R^(Q) is optionally substituted phenyl, wherein R^(Q)is optionally substituted with up to 4 substituents selected from R¹,R², R³, R⁴, or R⁵. In one embodiment, R^(Q) is phenyl optionallysubstituted with up to 3 substituents selected from halo, cyano,trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl. Exemplary R^(Q) include:

R^(Q)

In one embodiment, R^(Q) is optionally substituted naphthyl, whereinR^(Q) is optionally substituted with up to 4 substituents selected fromR¹, R², R³, R⁴, or R⁵. In one embodiment, R^(Q) is naphthyl optionallysubstituted with up to 5 substituents selected from halo, cyano,trifluoromethyl, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy,trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.

Or, R^(Q) is an optionally substituted 3-8 membered cycloaliphatic ring,wherein R^(Q) is optionally substituted with up to 4 substituentsselected from R¹, R², R³, R⁴, or R⁵. In one embodiment, R^(Q) isselected from optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

Or, R^(Q) is an optionally substituted 5-6 membered monocyclic,unsaturated, partially saturated, or aromatic ring containing up to 3heteroatoms independently selected from O, S, N, or NH. Or, R^(Q) is a3-7 membered monocyclic, heterocyclic ring.

In one embodiment, R^(Q) is selected from an optionally substituted ringselected from:

In another embodiment, R^(Q) is selected from any of rings a-1 to a-13or a-15, wherein said ring is fused to an optionally substituted phenylring.

In another embodiment, R^(Q) is selected from an optionally substitutedring selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.

In another embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is any one of the above rings a-16 to a-21,wherein said ring is fused to an optionally substituted phenyl ring.

In another embodiment R^(Q) is ring a-18, wherein said ring isoptionally substituted with a 3-6 membered monocyclic spirocyclic ringcontaining 0 to 3 heteroatoms independently selected from O, S, N, orNH; wherein said spirocyclic ring is optionally substituted with up to 4substituents independently selected from R¹, R², R³, R⁴ or R⁵; andwherein said spirocyclic ring is optionally fused to a pheny ringoptionally substituted with up to 4 substituents independently selectedfrom R¹, R², R³, R⁴, or R⁵.

In another embodiment, R^(Q) is an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from O, S, N, or NH, wherein R^(Q) isoptionally substituted with up to 4 substituents selected from R¹, R²,R³, R⁴, or R⁵. In one embodiment, R^(Q) is optionally substitutednaphthyl. Or, R^(Q) is an optionally substituted 8-10 membered,bicyclic, heteroaromatic ring. Or, R^(Q) is an optionally substituted,8-10 membered, bicyclic, heterocyclic ring.

In one embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is an optionally substituted ring selectedfrom:

In another embodiment, R^(Q) is an optionally substituted ring selectedfrom:

wherein ring D is a 3-6 membered spirocyclic ring containing 0 to 3heteroatoms independently selected from O, S, N, or NH; wherein ring Dis optionally substituted with up to 4 substituents independentlyselected from R¹, R², R³, R⁴ or R⁵; and wherein ring D is optionallyfused to a pheny ring optionally substituted with up to 4 substituentsindependently selected from R¹, R², R³, R⁴, or R⁵.

In another embodiment, ring D is pyrrolidine, piperidine,tetrahydropyran, tetrahydrofuran or cyclopentane.

In another embodiment, ring D is pyrrolidine, piperidine,tetrahydropyran, tetrahydrofuran or cyclopentane each fused to anoptionally substituted phenyl ring.

In another embodiment, R^(Q) is selected from the following:

In another embodiment, R^(Q) is selected from pyrrolidin-1-yl,3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, 3-methyl-piperidin-1-yl,4-methyl-piperidin-1-yl, 4,4-difluoropiperidin-1-yl,4,5-dimethyl-4-morpholin-1-yl, indol-1-yl, 5-chloro-indol-1-yl,tetrahydro-isoquinolin-2-yl, 7-chloro-tetrahydro-isoquinolin-2-yl,7-trifluoromethyl-tetrahydro-isoquinolin-2-yl,7-fluoro-tetrahydro-isoquinolin-2-yl,6-methyl-tetrahydro-isoquinolin-2-yl, 6-chloro-tetrahydroquino-1-yl,8-trifluoromethyl-quinolin-4-yl, pyridin-3-yl, or pyridin-4-yl.

In one embodiment, R^(Q) is

wherein ring B is a 5-7 membered heterocyclic or heteroaryl ring havinga single nitrogen heteroatom; wherein R^(Q) is optionally substitutedwith up to 4 substituents selected from R¹, R², or R³.

Exemplary embodiments of R^(Q) include:

R^(Q)

In one embodiment, x and y, each is 1-2.

In another embodiment, x is 0 and y is 3. Or, x is 1 and y is 2. Or, xand y, both are 2.

In one embodiment, ring A, together with W, Y₁ x and y is:

In another embodiment, ring A, together with W, Y₁, x and y is:

In another embodiment, ring A, together with W, Y₁, x and y is:

In another embodiment, ring A, together with W, Y₁, x and y is:

In another embodiment, ring A, together with W, Y₁, x and y is:

In another embodiment, ring A, together with W, Y₁, x and y is:

In another embodiment, ring A, together with W, Y₁, x and y is:

In one embodiment, the present invention provides compounds of formulaIA or formula IB:

wherein:

U and T each is independently CH or N; provided that both U and T arenot simultaneously N;

R²² is R¹ or R²;

R^(Z) is selected from R¹, R², or R⁵;

q is 0-2;

v is 0 or 1;

Q is C1-C4 alkylidene, wherein up to two non-adjacent methylene units ofQ are optionally and independently replaced by —CO—, —CS—, —COCO—,—CONR²—, —CONR²NR²—, —CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—,—NR²NR², —NR²NR²CO—, —NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—,—NR²SO₂NR²—, or a spirocycloalkylene moiety; and

R^(Q) is a C1-C6 aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from O, S, N, or NH, or an 8-15 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ring ortricyclic fused or spirocyclic ring system having 0-5 heteroatomsindependently selected from O, S, N, or NH;

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In one embodiment, R²² is oxo.

In another embodiment, R²² is C1-C4 alkyl. Exemplary embodiments includemethyl, ethyl, or propyl.

In some embodiments, Q is C1-C4 alkylidene, wherein one methylene unitsof Q is optionally replaced by —CO—, —CS—, —O—, —S—, —SO, —SO₂—, —NR²—,or a spirocycloalkylene moiety;

In another embodiment, R^(Q) is as defined above.

In one embodiment, the present invention provides compounds of formulaIA-i, formula IA-ii, formula IA-iii, formula IA-iv, formula IB-i,formula IB-ii, formula IB-iii, or formula IAB-iv:

wherein:

Q is C1-C4 straight or branched alkylidene, wherein up to one methyleneunit of Q is optionally and independently replaced by —O—;

T is CH or N;

U is CH or N;

R^(Q) is phenyl,

wherein ring B is a 5-7 membered heterocyclic or heteroaryl ring havinga single nitrogen heteroatom;

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R³.

In one embodiment, R^(Q) is selected from:

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R³.

In one embodiment, R^(Q) is phenyl optionally substituted with up to 4substituents independently selected from R¹, R², or R³.

In one embodiment, R^(Q) is

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R³.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In one embodiment, Q is C1-C4 straight or branched alkylidene. ExemplaryQ include —CH₂—, —CH₂—CH₂—, —CH(Me)—, —C(Me)₂-, —CH(i-Pr)—, etc.

In one embodiment of formula IA-i, formula IA-ii, formula IA-iii, orformula IA-iv:

-   -   U is CH and T is CH or N;    -   Q is —CH₂—, —CH₂—CH₂—, —CH(Me)—, or —C(Me)₂-; and    -   R^(Q) is ring b or ring c above, wherein R^(Q) is optionally        substituted with up to three substituents selected from chloro,        fluoro, or CF₃;

In one embodiment of formula IB-i, formula IB-ii, formula IB-iii, orformula IAB-iv:

-   -   U is CH and T is N;    -   Q is —CH₂—, —CH₂—CH₂—, —CH(Me)—, or —C(Me)₂-; and    -   R^(Q) is ring b or ring c above, wherein R^(Q) is optionally        substituted with up to three substituents selected from chloro,        fluoro, or CF₃;

In another embodiment, the present invention provides compounds offormula IIA or formula IIB:

wherein U, T, R²², R^(Z), z, q, v, Q and R^(Q) are as defined above.

In one embodiment of formula IIA or formula IIB, q is zero, and v is 1.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In one embodiment, Q is C1-C4 straight or branched alkylidene. ExemplaryQ include —CH₂—, —CH₂—CH₂—, —CH(Me)—, —C(Me)₂-, —CH(i-Pr)—, etc.

In one embodiment, z is 1, R²² is OH on the carbon atom directlyattached to the phenyl ring.

In one embodiment, R^(Q) is selected from:

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R⁴.

In one embodiment of formula IIA:

-   -   U is CH and T is CH or N;    -   q and z, both are zero;    -   v is 1;    -   Q is —CH₂—, —CH₂—CH₂—, or —CH(Me)—;    -   R^(Q) is ring b or ring f, optionally substituted with up to 3        halo substituents.

In one embodiment of formula IIB:

-   -   U is CH and T is N;    -   q and z, both are zero;    -   v is 1;    -   Q is —CH₂—, —CH₂—CH₂—, or —CH(Me)—;    -   R^(Q) is ring b or ring f, optionally substituted with up to 3        halo substituents.

In another embodiment, the present invention provides compounds offormula IIIA or formula IIIB:

wherein U, T, R²², R^(Z), z, q, v, Q and R^(Q) are as defined above.

In one embodiment of formula IIIA or formula IIIB, v, q, and z are bothzero.

In another embodiment, v is zero and Q is —CH₂—NH—C(O)(C1-C4alkylidene)-, —NH—C(O—(C1-C4 alkylidene)-. Exemplary Q include—NH—C(O)—CH₂—, —NH—C(O)—CH₂—CH₂—, —NH—C(O)—CH(Me)—, —CH₂—NH—C(O)CH(Me)—,—NH—C(O)—C(Me)₂-, —NH—C(O)—CH(i-Pr)—, etc.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In another embodiment, the present invention provides compounds offormula IVA or formula IVB:

wherein U, T, R²², R^(Z), z, q, v, Q and R^(Q) are as defined above.

In one embodiment of formula IVA or formula IVB, v, q, and z are bothzero.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In one embodiment, Q is NHC(O)C1-C4 straight or branched alkylidene,C1-C4 straight or branched alkylidene. Exemplary Q include —CH₂—,—CH₂—CH₂—, —CH(Me)—, —C(Me)₂-, —CH(i-Pr)—, —NHC(O)CH(Me)—, etc.

In one embodiment, R^(Q) is selected from:

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R⁴.

In one embodiment of compound of formula IVA or formula IVB:

-   -   Q is —CH₂—, —CH₂—CH₂—, —CH(Me)—, or —C(Me)₂-; and    -   R^(Q) is ring b above, wherein R^(Q) is optionally substituted        with up to three substituents selected from chloro, fluoro, or        CF₃;

In another embodiment, the present invention provides compounds offormula VA, formula VA-i, formula VB or formula VB-i:

wherein U, T, R²², R^(Z), z, q, v, Q and R^(Q) are as defined above.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In one embodiment of formula VA-i or formula VB-i, R^(Q) is selectedfrom:

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R⁴.

In one embodiment of formula VA-i or formula VB-i:

-   -   Q is —CH₂— or —CH(Me)—; and    -   R^(Q) is ring b above, wherein R^(Q) is optionally substituted        with up to three substituents selected from chloro, fluoro, or        CF₃.

In another embodiment, the present invention provides compounds offormula VIA or formula VIB:

wherein V is a bond, O, NR², or C(R²)₂ and U, T, R²², R^(Z), z, q, v, Qand IV are as defined above.

In some embodiments, V is a bond, O, or NH.

In one embodiment of formula VIA or formula VIB, v, q, and z are bothzero.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In one embodiment, v is 0, Q and V each is a bond, and x, y, z, R²²,together with the ring therein is:

R^(Q) is phenyl,

wherein ring B is a 5-7 membered heterocyclic or heteroaryl ring havinga single nitrogen heteroatom;

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R³.

In one embodiment, the present invention provides compounds of formulaVIA-i:

wherein:

U, T, R^(Z), and q are as defined above; and

R^(Q) is

wherein ring B is a 5-7 membered heterocyclic or heteroaryl ring havinga single nitrogen heteroatom; wherein R^(Q) is optionally substitutedwith up to 4 substituents independently selected from R¹, R², or R³.

In one embodiment, U and T, both are CH.

In another embodiment, U is CH and T is N.

In one embodiment, R^(Q) is selected from:

wherein R^(Q) is optionally substituted with up to 4 substituentsselected from R¹, R², or R³.

Exemplary R^(Q) in compounds of the present invention include:

R^(Q)

In one embodiment, the present invention provides compounds of formulaVIA-ii:

U, T, R^(Z), and q are as defined above; and

wherein R^(Q) is phenyl optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R³.

In one embodiment of formula VIA-ii, q is zero.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

Exemplary R^(Q) in compounds of the present invention include:

R^(Q)

In one embodiment, the present invention provides compounds of formulaVIA-iii:

wherein U, T, R^(Z), and q are as defined above; and

R^(Q) is

wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R³.

In one embodiment of formula VIA-iii q is zero.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

Exemplary R^(Q) in compounds of the present invention includeembodiments wherein said optionally substituted phenyl ring attached tosaid piperazine is selected from:

In one embodiment, the present invention provides compounds of formulaVIIA or formula VIIB:

wherein U, T, R^(Z), and R^(Q), q are as defined above.

In one embodiment of formula VIIA or formula VIIB, q is zero.

In one embodiment, T is CH. In another embodiment, T is N.

In one embodiment, U is N and T is CH.

In another embodiment, T is N and U is CH.

In another embodiment, U and T, both are CH.

In one embodiment, the present invention provides compounds of formulaVIIA-i or formula VIIB-i:

In one embodiment, the present invention provides compounds of formulaVIIA-ii or formula VIIB-ii:

In one embodiment, the present invention provides compounds of formulaVIIA-iii or formula VIIB-iii:

In one embodiment of formula VIIA-i or formula VIIA-ii, U is CH and T isN. Or, U and T both are CH.

In an alternative embodiment, the present invention provides compoundsof formula I′:

or a pharmaceutically acceptable salt thereof;

wherein:

ring Z is a 5-7 membered unsaturated or aromatic ring having 1-4 ringheteroatoms selected from O, S, or N, wherein Z is optionallysubstituted with up to q occurrences of R^(Z) substitutents, whereineach R^(Z) is independently selected from R¹, R², R³, R⁴, or R⁵; and qis 0-4;

ring C is a 5-7 membered carbocyclic or heterocyclic ring having 0-2ring atoms selected from O, S, or N, wherein ring C is fused to a phenylring; and

wherein said ring C together with said fused phenyl ring is optionallysubstituted with up to 5 substituents independently selected from R¹,R², R³, R⁴, or R⁵;

R¹¹ is R² or Y;

R²² is R¹, R², or R⁴;

R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), ═N—OR⁶, ═N—OR⁷, R⁶ or(CH₂)_(n)—Y;

-   -   n is 0, 1 or 2;    -   Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂,        NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; or        -   two R¹ on adjacent ring atoms, taken together, form            1,2-methylenedioxy or 1,2-ethylenedioxy;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R³ is optionally substituted with up to 3substituents, independently selected from R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶C(S)N(R⁶)₂, NR⁶C(S)NR⁵R⁶, NR⁶C(S)N(R⁵)₂,NR⁵C(S)N(R⁶)₂, NR⁵C(S)NR⁵R⁶, NR⁵C(S)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶,NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂,P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂,P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R³ is optionally substituted with up to 3R¹ substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR⁷ substituent;

R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R⁷ is optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic or (CH₂)_(m)—Z′wherein m is 0-2;

-   -   Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂,        CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6)        aliphatic, S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂,        NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)₂,        N((C1-C6)aliphatic)R⁸, COOH, C(O)O(—(C1-C6)aliphatic), or        O—(C1-C6)aliphatic; and

R⁸ is CH₃(C(O)—, C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.

In one embodiment, ring C is an optionally substituted ring selectedfrom:

Preferred embodiments of ring Z, R², R¹¹, R²², w, and z in compounds offormula I′ are as described above for compounds of formula I.

Exemplary compounds of the present invention are shown below in Table 2.

TABLE 2

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

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41

42

43

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47

48

49

50

51

52

53

54

55

56

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60

61

62

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64

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66

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68

69

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81

82

83

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86

87

88

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90

91

92

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94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

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118

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120

121

122

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124

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126

127

128

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477

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531

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533

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539

540

541

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555

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569

570

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611

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613

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619

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649

650

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653

654

655

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The compounds of the present invention may be prepared readily usingmethods known in the art. Illustrated below in Scheme 1 through Scheme 6are methods for preparing the compounds of the present invention.

Intermediates

1. A compound having formula N-1:

wherein:

ring Z is a 5-7 membered unsaturated or aromatic ring having 1-4 ringheteroatoms selected from O, S, or N, wherein Z is optionallysubstituted with up to q occurrences of R^(Z) substitutents, whereineach R^(Z) is independently selected from R¹, R², R³, R⁴, or R⁵; and qis 0-4;

w is 0-4;

z is 0-4;

P is —O-PG or a suitable leaving group;

PG is a suitable leaving group;

R¹¹ is R² or Y;

R²² is R¹, R², or R⁴;

R¹ is (CH₂)_(n)—Y;

-   -   n is 0, 1 or 2;    -   Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂,        NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R³ is optionally substituted with up to 3substituents independently selected from R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶C(S)N(R⁶)₂, NR⁶C(S)NR⁵R⁶, NR⁶C(S)N(R⁵)₂,NR⁵C(S)N(R⁶)₂, NR⁵C(S)NR⁵R⁶, NR⁵C(S)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶,NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂,P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂,P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R⁵ is optionally substituted with up to 3R¹ substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR⁷ substituent;

R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R⁷ is optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic or (CH₂)_(m)—Z′wherein m is 0-2;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6) aliphatic,S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂, NH—(C1-C6)aliphatic,N((C1-C6)aliphatic)₂, N((C1-C6)aliphatic)R⁸, COOH,C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and

R⁸ is CH₃C(O)—, C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.

In one embodiment, PG is a suitable protecting group. Exemplary suchleaving groups include methoxymethyl, methoxyethyl, tetrahydropyranyl,allycarbonate, trimethylsilyl, t-butyl-diphenylsilyl,t-butyl-dimethyl-silyl, acetate, benzoyl, benzyl, p-methoxybenzyl, etc.Other suitable protecting groups are well known to one of skill in theart, e.g., Greene, T. W.; Wuts, P. G. M. “Protecting Groups in OrganicSynthesis”, 3rd Ed; John Wiley & Sons, Inc.: New York, 1999; Chapter 2,p 17-245.

In another embodiment, P is a suitable leaving group. A suitable leavinggroup, as used herein is a group capable of displacement. See, “AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure,” pp. 339-357,Jerry March, 4^(th) Ed., John Wiley & Sons (1992).

Exemplary such leaving groups include trifluoromethanesulfonate,methanesulfonate, tosylate, halo, etc. Other suitable leaving groups arewell known to one of skill in the art.

In another embodiment, the present invention provides compounds offormula N-2:

wherein:

ring Z is a 5-7 membered unsaturated or aromatic ring having 1-4 ringheteroatoms selected from O, S, or N, wherein Z is optionallysubstituted with up to q occurrences of R^(Z) substitutents, whereineach R^(Z) is independently selected from R¹, R², R³, R⁴, or R⁵; and qis 0-4;

w is 0-4;

PG is a suitable protecting group;

R¹¹ is R² or Y;

R²² is R¹, R², or R⁴;

R¹ is (CH₂)_(n)—Y;

-   -   n is 0, 1 or 2;    -   Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂,        NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R³ is optionally substituted with up to 3substituents, independently selected from R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶C(S)N(R⁶)₂, NR⁶C(S)NR⁵R⁶, NR⁶C(S)N(R⁵)₂,NR⁵C(S)N(R⁶)₂, NR⁵C(S)NR⁵R⁶, NR⁵C(S)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶,NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂,P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂,P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R⁵ is optionally substituted with up to 3R¹ substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR⁷ substituent;

R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R⁷ is optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2;

-   -   Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂,        CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6)        aliphatic, S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂,        NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)₂,        N((C₁-C6)aliphatic)R⁸, COOH, C(O)O(—(C1-C6)aliphatic), or        O—(C1-C6)aliphatic; and

R⁸ is CH₃C(O)—, C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.

In one embodiment, P is a suitable protecting group. Exemplary suchleaving groups include methoxymethyl, methoxyethyl, tetrahydropyranyl,allycarbonate, trimethylsilyl, t-butyl-diphenylsilyl,t-butyl-dimethylsilyl, acetate, benzoyl, benzyl, p-methoxybenzyl, etc.Other suitable protecting groups are well known to one of skill in theart, e.g., Green, T. W.; Wuts, P. G. M. “Protecting Groups in OrganicSynthesis”, 3rd Ed; John Wiley & Sons, Inc.: New York, 1999; Chapter 2,p 17-245.

In another embodiment, the present invention provides compounds havingformula N-3:

wherein:

-   -   ring Z is a 5-7 membered unsaturated or aromatic ring having 1-4        ring heteroatoms selected from O, S, or N, wherein Z is        optionally substituted with up to q occurrences of R^(Z)        substitutents, wherein each R^(Z) is independently selected from        R¹, R², R³, R⁴, or R⁵; and q is 0-4;

w is 0-4;

R¹¹ is R² or Y;

R²² is R¹, R², or R⁴;

R¹ is (CH₂)_(n)—Y;

-   -   n is 0, 1 or 2;    -   Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂,        NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R³ is optionally substituted with up to 3substituents independently selected from R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶),NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵,NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂,NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶C(S)N(R⁶)₂, NR⁶C(S)NR⁵R⁶, NR⁶C(S)N(R⁵)₂,NR⁵C(S)N(R⁶)₂, NR⁵C(S)NR⁵R⁶, NR⁵C(S)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶,NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂,P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂,P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R⁵ is optionally substituted with up to 3R¹ substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR⁷ substituent;

R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R⁷ is optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2;

-   -   Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂,        CH₂(halo), —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6)        aliphatic, S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂,        NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)₂,        N((C₁-C6)aliphatic)R⁸, COOH, C(O)O(—(C1-C6)aliphatic), or        O—(C1-C6)aliphatic; and

R⁸ is CH₃C(O)—, C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.

In yet another embodiment, the present invention provides compoundshaving formula N-4:

wherein:

J is

wherein L is —CH═CH—, —CH₂—CH₂—, or —CH₂—CH₂—CH₂—;

wherein J is optionally substituted with up to 4 substituentsindependently selected from R¹, R², or R³;

R¹¹ is R² or Y;

R²² is R¹, R², or R⁴;

R¹ is (CH₂)_(n)—Y;

-   -   n is 0, 1 or 2;    -   Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂,        NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶;

R² is hydrogen or C1-C6 aliphatic, wherein each R² is optionallysubstituted with up to 2 substituents independently selected from R¹,R⁴, or R⁵;

R³ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R³ is optionally substituted with up to 3substituents, independently selected from R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂,OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵),SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶,SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵,C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵, NR⁵C(O)OR⁵,NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂, NR⁵C(O)NR⁵R⁶,NR⁵C(O)N(R⁵)₂, NR⁶C(S)N(R⁶)₂, NR⁶C(S)NR⁵R⁶, NR⁶C(S)N(R⁵)₂,NR⁵C(S)N(R⁶)₂, NR⁵C(S)NR⁵R⁶, NR⁵C(S)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶,NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂,P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂,P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵);

R⁵ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R⁵ is optionally substituted with up to 3R¹ substituents;

R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionally substituted with aR⁷ substituent;

R⁷ is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, and each R⁷ is optionally substituted with up to 2substituents independently selected from C1-C6 aliphatic, or(CH₂)_(m)—Z′ wherein m is 0-2;

Z′ is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo),—OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6) aliphatic,S(O)—(C1-C6) aliphatic, SO₂—(C1-C6)aliphatic, NH₂, NH—(C1-C6)aliphatic,N((C1-C6)aliphatic)₂, N((C1-C6)aliphatic)R⁸, COOH,C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and

R⁸ is CH₃C(O)—, C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.

In compounds of formula N-1, formula N2, formula N-3, and formula N-4,the preferred embodiments of ring Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R¹¹, R²², w, and Z are as described above for compounds of formula I.

USES, FORMULATION AND ADMINISTRATION

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of voltage-gated sodium ion channels, and thus the presentcompounds are useful for the treatment of diseases, disorders, andconditions including, but not limited to acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, and incontinence. Accordingly, in another aspect of thepresent invention, pharmaceutically acceptable compositions areprovided, wherein these compositions comprise any of the compounds asdescribed herein, and optionally comprise a pharmaceutically acceptablecarrier, adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a subject in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, dipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method of treatment or lessening the severityof stroke, cerebral ischemia, traumatic brain injury, amyotrophiclateral sclerosis, stress- or exercise induced angina, palpitations,hypertension, migraine, or abnormal gastro-intestinal motility isprovided comprising administering an effective amount of a compound, ora pharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain isprovided comprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof. Incertain other embodiments, a method for the treatment or lessening theseverity of radicular pain, sciatica, back pain, head pain, or neck painis provided comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof. In still other embodiments, a method for the treatment orlessening the severity of severe or intractable pain, acute pain,postsurgical pain, back pain, tinnitis or cancer pain is providedcomprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,including, abdominal; pancreatic; IBS pain; chronic and acute headachepain; migraine; tension headache, including, cluster headaches; chronicand acute neuropathic pain, including, post-herpetic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac Pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cyctitis (IC); or prostatitis; complexregional pain syndrome (CRPS), type I and type II; angina-induced painis provided, comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the subject to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “subject”, as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels. In one embodiment,the compounds and compositions of the invention are inhibitors of one ormore of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,or NaV1.9, and thus, without wishing to be bound by any particulartheory, the compounds and compositions are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation or hyperactivity of one or more of NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as a“NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder”. Accordingly, in anotheraspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicated in thedisease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.3 and/or NaV1.1.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9, activity in a biological sample or a subject, which methodcomprises administering to the subject, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9, activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to, thestudy of sodium ion channels in biological and pathological phenomena;and the comparative evaluation of new sodium ion channel inhibitors.

EXAMPLES

General Methods

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were obtained assolutions in deuteriochloroform (CDCl₃) or dimethyl sulfoxide-D₆ (DMSO).Mass spectra (MS) were obtained using an Applied Biosystems API EX LC/MSsystem equipped with a Phenomenex 50×4.60 mm luna-5μ C18 column. TheLC/MS eluting system was 10-99% acetonitrile in H₂O with 0.035% v/vtrifluoroacetic acid using a 4.5 minute linear gradient and a flow rateof 4.0 mL/minute. Silica gel chromatography was performed using silicagel-60 with a particle size of 230-400 mesh. Pyridine, dichloromethane(CH₂Cl₂), tetrahydrofuran (THF), were from Aldrich Sure-Seal bottleskept under dry nitrogen. All reactions were stirred magnetically unlessotherwise noted. Unless specified otherwise, all temperatures refer tointernal reaction temperatures.

Example 1 2,2,2-Trifluoro-1-(4-phenylpiperazin-1-yl)ethanone

Under an N₂ atmosphere at −78° C., 2,2,2-trifluoroacetic anhydride (5.6g, 4.3 mL, 30.8 mmol) was added dropwise to a solution of1-phenylpiperazine (5.0 g, 4.7 mL, 30.8 mmol), triethylamine (3.1 g, 4.3mL, 30.8 mmol), and CH₂Cl₂ (50 mL). The reaction was allowed to warm toRT over a period of 30 minutes. After evaporating the solvents underreduced pressure, purification via silica gel chromatography using 7/3hexanes/EtOAc gave 2,2,2-trifluoro-1-(4-phenylpiperazin-1-yl)ethanone asa white solid (6.1 g, 62%). ¹H NMR (400 MHz, DMSO-d6) δ 7.27-7.23 (m,2H), 6.98-6.96 (m, 2H), 6.86-6.82 (m, 1H), 3.74-3.69 (m, 4H), 3.24-3.21(m, 4H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=258.90; t_(R)=3.06 min.

4-(4-(2,2,2-Trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride

A mixture of 2,2,2-trifluoro-1-(4-phenylpiperazin-1-yl)ethanone (1.0 g,3.9 mmol) and chlorosulfonic acid (6 mL) was heated at 155° C. for 15min. After cooling to RT, the mixture was poured into ice water andextracted with EtOAc. The organic layer was concentrated and purifiedvia silica gel chromatography using 7/3 hexanes/EtOAc to obtain4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chlorideas a yellow solid (1.0 g, 72%). ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.89 (m,2H), 6.96-6.92 (m, 2H), 3.88 (t, J=5.3 Hz, 2H), 3.83 (t, J=5.1 Hz, 2H),3.55-3.52 (m, 4H).

General Procedure 1

Under an N₂ atmosphere, a mixture of the sulfonyl chloride (1 mmol) andaminoheterocycle (1 mmol), and pyridine (1.0 mL) was stirred at RT for19 h. The crude product was purified via silica gel chromatography usingMeOH in CH₂Cl₂.

N-(Thiazol-2-yl)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzenesulfonamide

Synthesized according to general procedure 1. The crude product waspurified via silica gel chromatography using 3% MeOH in CH₂Cl₂. Theresulting oil was taken up in a 2:1 mixture of CH₂Cl₂:Et₂O (12 mL) andcooled at 0° C. for 20 minutes. The formed precipitate was filtered offand dried under vacuum to obtainN-(thiazol-2-yl)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzenesulfonamideas a white solid (280 mg, 28%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=421.10; t_(R)=2.68 min.

Synthesis of 1,2,4-Thiadiazol-5-ylamine Method A(E)-N′-Carbamothioyl-N,N-dimethylformimidamide

Under an N₂ atmosphere at RT, 1,1-dimethoxy-N,N-dimethylmethanamine (174mL, 150 g, 1.31 mol) was added to a mixture of thiourea (90.0 g, 1.2mol) and MeOH (950 mL), and the reaction was heated to reflux for 4 h.The mixture was allowed to cool to RT and stirred for 19 h. The reactionwas then cooled to 0° C. and stirred for 1 h. The formed precipitate wasfiltered off and washed with a 1:1 mixture of MeOH and hexanes to obtain(E)-N′-carbamothioyl-N,N-dimethylformimidamide as a white solid (133 g,85%). ¹H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.20 (s, 1H), 7.93 (s,1H), 3.13 (s, 3H), 2.99 (s, 3H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=132.0; t_(R)=0.37 min.

1,2,4-Thiadiazol-5-ylamine

A mixture of (E)-N′-carbamothioyl-N,N-dimethylformimidamide (3.9 g, 30mmol), hydroxylamine-O-sulfonic acid (3.7 g, 33 mmol) and EtOH (100 mL)was heated at 80° C. for 8 h. After cooling to RT, triethylamine wasadded, and the mixture was stirred at RT for 19 h. The solvents wereevaporated under reduced pressure, and the residue was taken up in a 9:1mixture of CH₂Cl₂:MeOH (10 mL) and purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ to obtain1,2,4-thiadiazol-5-amine as a white solid (1.4 g, 47%). ¹H NMR (400 MHz,DMSO-d6) δ 7.95 (s, 2H), 7.85 (s, 1H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=102.1; t_(R)=0.39 min.

Method B 1,2,4-Thiadiazol-5-ylamine

To a solution of formamidine (HOAc salt, 500 g, 4.8 mol) in MeOH (1500mL) was added potassium thiocyanate (465 g, 4.8 mol). After stirring atroom temperature for 10 min, a solution of sodium methoxide (520 g, 9.6mol) in MeOH (1500 mL) was added to the resulting solution at 0° C., andthen bromine (250 mL, 4.8 mol) was added dropwise to the solution at−15° C. After stirring at −10° C. for 0.5 h, 0° C. for 0.5 h, and atroom temperature for 3 h, MeOH was removed under reduced pressure. Theresidue was dissolved in EtOAc, and the insoluble material was filtered.The filtrate was poured into a saturated aqueous NaCl solution, and theaqueous layer was extracted with EtOAc. The organic layer was dried overNa₂SO₄ and evaporated under reduced pressure. The residual gum wasextracted with Et₂O to give the crude compound[1,2,4]thiadiazol-5-ylamine (221 g), which was used in the next stepwithout further purification.

1,2,4-Thiadiazol-5-ylamine hydrochloride

To a solution of 1,2,4-thiadiazol-5-ylamine (220 g, 2.19 mol) in MeOH(1000 mL) was added solution of HCl in MeOH (4 M, 1000 mL). Afteraddition, the resulting suspension was stirred at room temperature for 1h. The solid product was collected by filtration, washed with MeOH, anddried to give 1,2,4-thiadiazol-5-amine hydrochloride (137.7 g, 21% overtwo steps). ¹H NMR (300 MHz, D₂O) δ 8.02 (s, 1H). MS (ESI) m/e (M+H⁺)101.2.

N-(1,2,4-Thiadiazol-5-yl)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzenesulfonamide

Synthesized according to general procedure 1. The crude product waspurified via silica gel chromatography using 5% MeOH in CH₂Cl₂ andtriturated with a 2:1 mixture of CH₂Cl₂:Et₂O to obtainN-(1,2,4-thiadiazol-5-yl)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzenesulfonamideas a white solid (900 mg, 20%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=422.30; t_(R)=2.80 min.

General Procedure 2

A solution of sulfonamide (1 equivalent), NaOH (10 equivalents), and H₂O(0.25 M) was stirred at RT for 1 h, then cooled to 0° C. Acetic acid (10equivalents) was added, and the reaction was stirred at 0° C. for 20min. The formed precipitate was filtered off and dried under vacuum togive the desired product.

4-(piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 2. ¹H NMR (400 MHz, DMSO-d6)δ 7.59 (d, J=8.9 Hz, 2H), 7.09 (d, J=4.3 Hz, 1H), 6.95 (d, J=9.0 Hz,2H), 6.62 (d, J=4.3 Hz, 1H), 3.25 (t, J=5.1 Hz, 4H), 2.96 (t, J=5.1 Hz,4H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=325.30; t_(R)=0.44 min.

4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 2. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=326.1; t_(R)=0.64 min. ¹HNMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.59 (d, J=8.9 Hz, 2H), 6.98 (d,J=9.0 Hz, 2H), 3.41-3.38 (m, 4H), 3.20-3.18 (m, 4H).

General Procedure 3: Method A

A mixture of 4-bromobenzene-1-sulfonyl chloride (1 equivalent), aminoheterocycle (1 equivalent) and pyridine (2.2-4.4 M) was stirred under anN₂ atmosphere at RT for 19 h. Purification via silica gel chromatographyusing 5% MeOH in CH₂Cl₂ gave the desired product.

General Procedure 3: Method B

A mixture of 4-bromobenzene-1-sulfonyl chloride (1 equivalent, 1 mmol),amino heterocycle (1 equivalent, 1 mmol), 1,4-diazabicyclo[2.2.2]octane(DABCO) (1 equivalent, 1 mmol) and acetonitrile (4.8 mL) was stirred atRT overnight. Purification via silica gel chromatography using MeOH inCH₂Cl₂ gave the desired products.

4-Bromo-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 3, method A. Yield: 99%. ¹HNMR (400 MHz, DMSO-d6) δ 7.77-7.71 (m, 4H), 7.29 (d, J=4.6 Hz, 1H), 6.87(d, J=4.6 Hz, 1H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=319.0; t_(R)=3.22 min.

4-Bromo-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 3, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=313.9; t_(R)=1.91 min.

General Procedure 4

A mixture of 4-bromobenzenesulfonamide (1 equivalent), piperazine (1-10equivalents), Pd₂(dba)₃ (0.02-0.075 equivalents),2-(di-t-butylphosphino)biphenyl (0.08-0.2 equivalents), NaO-tBu (2-6equivalents) and toluene (0.1-0.4 M of 4-bromobenzenesulfonamide) washeated at 80° C. for 2-6 h. Purification via silica gel chromatographyusing 10% MeOH in CH₂Cl₂ (with addition of 1-2% triethylamine) gave thedesired product.

4-(piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 4. The reaction was set upwith 1.6 mmol 4-bromo-N-(pyrimidin-4-yl)benzenesulfonamide, 16.0 mmolpiperazine, 0.12 mmol Pd₂(dba)₃, 0.15 mmol of2-(di-t-butylphosphino)biphenyl, 10 mmol of NaO-tBu and 12 ml, toluene.For the purification, 10% MeOH in CH₂Cl₂ without the addition oftriethylamine was used as a solvent system. Yield: 430 mg (84%). LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=320.2;t_(R)=0.42 min.

General Procedure 5: Method A

A solution of the sulfonamide (1 equivalent), BOP-reagent (1-1.5equivalent), triethylamine (1-1.5 equivalent), and carboxylic acid(1-1.5 equivalent) in DMF (0.3-0.5 M) was stirred under an N₂ atmosphereat RT for 19 h. Purification via reverse phase HPLC using 10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

General Procedure 5: Method B

To the carboxylic acid (1.5 equivalent, 0.17 mmol) and NaHCO₃ (1.5equivalent, 0.17 mmol) was added HATU (1.5 equivalent, 0.17 mmol) in DMF(0.15-0.25M, 0.25 mL). A solution of sulfonamide (1 equivalent, 0.11mmol) in DMF (0.15-0.25M, 0.25 mL) was then added and the reactionmixture was stirred at RT for 19 h. Purification via reverse phase HPLCusing 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

(2R)-2-(4-Fluoro-indol-1-yl)-propionic acid

To a cooled (0-5° C.) solution of 4-fluoro-indole (44.2 g, 327 mmol) indry DMF (400 mL) was added sodium hydride (55-65% dispersion in mineraloil, 36 g, 817 mmol) in portions. The resulting suspension was stirredat 0-5° C. for 20 minutes. (2S)-(−)-2-Bromopropionic acid (31.8 mL, 343mmol) was added dropwise. During the addition, the temperature was keptbelow 10° C. by cooling in an ice-bath. Upon completion of addition, themixture was stirred at RT for 2 hours. The mixture was poured into water(1300 mL), and the aqueous solution was washed with heptanes (400 mL)and EtOAc (2×400 mL). The aqueous layer was acidified with concentratedaqueous HCl solution (85 mL, pH<1), and extracted with EtOAc (2×400 mL).The combined organic layers were washed with 1 N aq. HCl solution (2×300mL) and with a saturated aqueous NaCl solution (300 mL). The solutionwas dried over sodium sulfate, filtered, and evaporated to dryness toafford a yellow oil (67.6 g, 99%, 82% ee). This oil (67.6 g, 323 mmol)was dissolved in 200 mL n-butyl acetate and(5)-L-(−)-α-methylbenzylamine (41.1 mL, 323 mmol) was added to the warm(50° C.) solution. The mixture was left crystallizing over the weekend.The formed solid was collected by filtration and washed with butylacetate and heptanes (2×) (68.7 g, 91% ee). This material wasrecrystallized twice from 500 mL water/15% ethanol (1^(st) recr.: 95%ee, 2^(nd) recr.: 97.5% ee). This material was dissolved in EtOAc (300mL) and washed with 1 N aqueous HCl (2×200 mL) and saturated aqueousNaCl solution (200 mL), dried over sodium sulfate, filtered, andevaporated to dryness giving (2R)-2-(4-fluoro-indol-1-yl)-propionic acid(18.7 g, 28%) as a greenish oil (purity: 97.5%).

(R)-4-(4-(2-(4-Fluoro-1H-indol-1-yl)propanoyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 5, method A. The reaction wasset up with 0.08 mmol4-(piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide, 0.08 mmol(2R)-2-(4-fluoro-indol-1-yl)-propionic acid, 0.08 mmol BOP reagent, 0.08mmol triethylamine and 200 μL DMF. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=514.50; t_(R)=3.03 min.

(R)-4-{4-[2-(4-Fluoro-1H-indol-1-yl)propionyl]piperazin-1-yl}-N-[1,2,4]thiadiazol-5-ylbenzenesulfonamide

Synthesized according to general procedure 5, method B. The reaction wasset up with 0.61 mmol4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 0.61mmol(2R)-2-(4-fluoro-indol-1-yl)-propionic acid, 0.61 mmol HATU, 0.61mmol N,N-diisopropyl ethyl amine and 2 mL (1:1) DMF:methylene dichlorideto get(R)-4-{-4-[2-(4-Fluoro-1H-indol-1-yl)propionyl]piperazin-1-yl}-N-[1,2,4]thiadiazol-5-ylbenzenesulfonamide as a white solid (200 mg, 63% yield). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=515.3; t_(R)=3.16 min.¹H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.47(s, 1H), 7.37 (s, 1H), 7.15-7.09 (m, 1H), 6.94 (d, J=9.1 Hz, 2H),6.84-6.79 (m, 1H), 6.54 (d, J=3.2 Hz, 1H), 5.87-5.82 (m, 1H), 3.66 (d,J=4.6 Hz, 2H), 3.58-3.53 (m, 2H), 3.17-3.09 (m, 4H), 1.59 (s, 3H).

2-(3-Chloro-4-fluorophenoxy)acetic acid

To a stirring solution of finely ground KOH (1.2 g, 20.4 mmol) in DMSO(6 mL) was added 3-chloro-4-fluorophenol (1.0 g, 6.8 mmol). The mixturewas stirred for 10 minutes at RT, then cooled to 0° C. Methylbromoacetate (1.25 g, 8.2 mmol) was added, and the reaction was slowlywarmed to RT and stirred overnight. H₂O (10 mL) and MeOH (10 mL) wereadded to the mixture, and the reaction was stirred for 1 h. Afterremoving MeOH under reduced pressure, H₂O (100 mL) and Et₂O (50 mL) wereadded, and the layers were separated. The aqueous phase was acidified topH 2 with an aqueous concentrated HCl solution and extracted with CH₂Cl₂(200 mL). The organic layer was dried over MgSO₄, filtered,concentrated, and dried to give 2-(3-chloro-4-fluorophenoxy)acetic acidas a white solid (1.1 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (t, J=8.8Hz, 1H), 7.01-6.98 (m, 1H), 6.84-6.80 (m, 1H), 4.68 (s, 2H).

4-(4-(2-(3-Chloro-4-fluorophenoxy)acetyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 5, method A. The reaction wasset up with 0.08 mmol4-(piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide, 0.08 mmol2-(3-chloro-4-fluorophenoxy)acetic acid, 0.08 mmol BOP reagent, 0.08mmol triethylamine and 200 μL DMF. ¹H NMR (400 MHz, DMSO-d6) δ 7.62 (d,J=9.0 Hz, 2H), 7.33 (t, J=9.1 Hz, 1H), 7.23-7.19 (m, 2H), 7.01 (d, J=9.1Hz, 2H), 6.97-6.93 (m, 1H), 6.78 (d, J=4.5 Hz, 1H), 4.92 (s, 2H), 3.58(t, J=5.0 Hz, 4H), 3.30 (d, J=5.0 Hz, 4H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=511.30; t_(R)=2.95 min.

6-Chloro-1,2,3,4-tetrahydroquinoline

A flask filled with a mixture of 6-chloroquinoline (12.0 g, 73.3 mmol),PtO₂ (2.16 g, 13 mol %), and MeOH (500 mL, 6.15 M) was flushed with N₂and then equipped with a balloon filled with H₂. The reaction was keptunder H₂ atmosphere and stirred for 4 h. The mixture was filteredthrough Celite and washed with CH₂Cl₂. Purification via silica gelchromatography using 50% CH₂Cl₂ in hexanes gave6-chloro-1,2,3,4-tetrahydroquinoline (7.7 g, 62%). ¹H NMR (400 MHz,DMSO-d6) δ 6.85-6.83 (m, 2H), 6.42-6.39 (m, 1H), 5.82 (s, 1H), 3.17-3.13(m, 2H), 2.64 (t, J=6.3 Hz, 2H), 1.78-1.72 (m, 2H). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=168.2; t_(R)=1.57 min.

(R)-Ethyl 2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoate

Under an N₂ atmosphere at RT, ethyl-O-trifluoromethylsulfonyl-L-lactate(1.2 mL, 6.56 mmol) was slowly added to a stirring solution of6-chloro-1,2,3,4-tetrahydroquinoline (1.0 g, 5.97 mmol) and 2,6-lutidine(0.8 mL, 6.87 mmol) in 1,2-dichloroethane (15 mL), and the reaction washeated at 70° C. overnight. The mixture was washed with H₂O andextracted twice with CH₂Cl₂. The organic layer was dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 0-20% EtOAc in hexanes gave (R)-ethyl2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoate as a yellow oil(1.54 g, 96%). ¹H NMR (300 MHz, CDCl₃): δ 6.9 (m, 2H), 6.46 (d, 1H), 4.4(q, 1H), 4.16 (m, 2H), 3.29 (m, 2H), 2.71 (m, 2H), 1.93 (m, 2H), 1.49(d, 3H), 1.22 (t, 3H).

(R)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoic acid

At 0° C., an aqueous 2.0 M KOH solution (7.5 mL, 14.9 mmol) was added toa stirring solution of (R)-ethyl2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoate (1.0 g, 3.73 mmol)in MeOH (7.5 mL). The reaction was allowed to warm to RT and leftstirring overnight. Due to the instability of the final product as asolid, the solution containing(R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoic acid was used forthe next step without further work up.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 5, method B. The reaction wasset up with 4.5 mmol4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 4.5 mmol(R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoic acid, 5.5 mmolHATU, 5.4 mmol sodium bicarbonate and 12 mL (1:1) DMF:methylenedichloride to get(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamideas a white solid (1.5 g, 61% yield). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=547.5; t_(R)=3.44 min. ¹H NMR (400MHz, DMSO-d6) δ 8.48 (s, 1H), 7.58 (d, J=9.1 Hz, 2H), 7.04-6.96 (m, 4H),6.78 (d, J=9.1 Hz, 1H), 4.88-4.84 (m, 1H), 3.73-3.69 (m, 1H), 3.58-3.53(m, 1H), 3.43-3.37 (m, 4H), 3.26-3.18 (m, 2H), 3.11-2.95 (m, 2H),2.73-2.64 (m, 2H), 1.84-1.73 (m, 2H), 1.84-1.08 (m, 3H).

3-(5-Chloro-1H-indol-1-yl)propanoic acid

Under an N₂ atmosphere, crushed KOH was added to a solution of5-chloro-1H-indole (2.0 g, 13.2 mmol) in DMSO (19 mL, 0.7 M), and themixture was stirred for 2 h at RT. Methyl 3-bromopropanoate (1.9 mL,17.2 mmol) was added dropwise, and the reaction was continued to stir atRT overnight. After diluting with H₂O, the reaction was cleared with a4.5 N aqueous KOH solution and washed 3 times with CH₂Cl₂. The aqueouslayer was acidified with a 2N HCl solution to pH 3 and extracted 3 timeswith CH₂Cl₂. The organic fractions were combined, dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 0-8% MeOH in CH₂Cl₂ gave 3-(5-chloro-1H-indol-1-yl)propanoic acid(2 g, 68%). ¹H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.54 (d,J=8.7 Hz, 1H), 7.44 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.7, 2.1 Hz, 1H),6.42 (dd, J=3.2, 0.7 Hz, 1H), 4.40 (t, J=6.8 Hz, 2H), 2.75 (t, J=6.8 Hz,2H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=224.5; t_(R)=2.74 min.

4-(4-(3-(5-Chloro-1H-indol-1-yl)propanoyl)piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 5, method A. The reaction wasset up with 0.11 mmol4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 0.11mmol 3-(5-chloro-1H-indol-1-yl)propanoic acid, 0.11 mmol BOP reagent,0.11 mmol triethylamine and 250 μL DMF. Yield 53%. ¹H NMR (400 MHz,DMSO-d6) δ 8.42 (s, 1H), 7.61-7.46 (m, 5H), 7.12 (dd, J=8.7, 2.1 Hz,1H), 6.97 (d, J=9.1 Hz, 2H), 6.40 (d, J=2.5 Hz, 1H), 4.43 (t, J=6.8 Hz,2H), 3.55 (t, J=5.2 Hz, 2H), 3.44 (t, J=4.9 Hz, 2H), 3.22 (t, J=5.1 Hz,2H), 3.17 (t, J=5.0 Hz, 2H), 2.83-2.79 (m, 2H). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=531.1; t_(R)=3.15 min.

4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 5, method A. The reaction wasset up with 0.11 mmol4-(piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide, 0.17 mmol2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoic acid, 0.17 mmol BOPreagent, 0.17 mmol triethylamine and 300 μL DMF. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=541.1; t_(R)=3.11 min.

4-(4-(3-(5-Chloro-1H-indol-1-yl)propanoyl)piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 5, method A. The reaction wasset up with 0.11 mmol4-(piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide, 0.17 mmol3-(5-chloro-1H-indol-1-yl)propanoic acid, 0.17 mmol BOP reagent, 0.17mmol triethylamine and 300 μL DMF. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=525.2; t_(R)=2.87 min.

4-{4-[2-(2,3-Dichloro-phenoxy)-propionyl]piperazin-1-yl}-N-pyrimidin-4-yl-benzenesulfonamide

Synthesized according to general procedure 5, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=536.3; t_(R)=2.71 min.

4-{4-[2-(4-Chloro-2-methyl-phenoxy)-acetyl]-piperazin-1-yl}-N-pyrimidin-4-yl-benzenesulfonamide

Synthesized according to general procedure 5, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=502.0; t_(R)=2.65 min.

General Procedure 6

A mixture of 4-bromosulfonamide (1 equivalent), piperazine (1-10equivalents), Pd₂(dba)₃ (0.02-0.075 equivalents),2-(di-t-butylphosphino)biphenyl (0.08-0.2 equivalents), NaO-tBu (2-6equivalents) and toluene (0.1-0.4 M of 4-bromobenzenesulfonamide) washeated at 80° C. for 2-6 h. Purification via silica gel chromatographyusing 10% MeOH in CH₂Cl₂ (with addition of 1-2% triethylamine) gave thedesired product.

4-{1-[3,4-methylenedioxybenzyl]-piperazin-1-yl}-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 6. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=459.3; t_(R)=2.2 min.

4-{1-[2-fluorophenyl]-piperazin-1-yl}-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 6. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=419.3; t_(R)=2.95 min.

(R)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperizin-1-yl)propan-1-one

To a 0° C. solution of(R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-propanoic acid (16.91 g,57 mmol) in a (1:1) mixture of methylene dichloride and DMF (150 mL),was added HATU (21.7 g, 57 mmol). The reaction mixture was stirred atthis temperature for 10 minutes. To this was added, 1-phenylpiperazine(8.7 mL, 57 mmol), followed by addition of sodium bicarbonate (4.79 g,57 mmol). Upon completion of addition, the mixture was stirred at 0° C.for 4 hours. The reaction mixture was diluted with 250 mL of methylenechloride and washed with water (1500 mL) and 1M HCl solution (2×250 mL).The organic layer was dried over magnesium sulfate, filtered, andconcentrated. Purification via silica gel chromatography using 20-50%ethyl acetate in hexane gave(R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperizin-1-yl)propan-1-oneas a white solid (11.84 g, 54%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=384.3; t_(R)=3.59 min.

4-(4-((R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonylchloride

To a 0° C. solution of chlorosulfonic acid, was added(R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperazin-1-yl)propan-1-oneover 5 minutes. The resultant solution was heated to 120° C. for 2 hrs.The reaction mixture was cooled and carefully poured into ice-water (750mL). The solution was extracted with methylene chloride (4×250 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated. Purification via silica gel chromatography using 40-70%ethyl acetate in hexane gave4-(4-((R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonylchloride as a yellow oil (760 mg, 10%). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=482.3; t_(R)=3.65 min.

General Procedure 7: Method A

A solution of 4-(4-((R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonyl chloride (1 equivalent),phosphazene base P1-t-Bu-tris(tetramethylene) (5 equivalents), and amine(1 equivalent) in acetonitrile (0.3-0.5 M) was stirred under an N₂atmosphere at RT for 19 h. Purification via reverse phase HPLC using10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

General Procedure 7: Method B

A solution of4-(4-((R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonylchloride (1 equivalent), DABCO (5 equivalents), and amine (1 equivalent)in acetonitrile (0.3-0.5 M) was stirred under an N₂ atmosphere at RT for19 h. Purification via reverse phase HPLC using 10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA) gave the desired product.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 7: method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=547; t_(R)=3.09 min.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(3-methylisothiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 7: method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=560; t_(R)=3.31 min.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(6-chloropyridazin-3-yl)benzenesulfonamide

Synthesized according to general procedure: 7 method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=560; t_(R)=3.31 min.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(6-chloropyrazin-2-yl)benzenesulfonamide

Synthesized according to general procedure: 7 method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=575.2; t_(R)=3.45 min.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(2-methylpyrimidin-4-yl)

Synthesized according to general procedure 7: method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=555.3; t_(R)=2.49 min.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(6-methylpyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 7: method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=555.3; t_(R)=2.57 min.

Example 2 General Procedure 8

A mixture of 4-bromobenzenesulfonamide (1 equivalent),2-methylpiperazine (1-10 equivalents), Pd₂(dba)₃ (0.02-0.075equivalents), 2-(di-t-butylphosphino)biphenyl (0.08-0.2 equivalents),NaO-tBu (2-6 equivalents) and toluene (0.1-0.4 M of4-bromobenzenesulfonamide) was heated at 80° C. for 2-6 h. Purificationvia silica gel chromatography using 10% MeOH in CH₂Cl₂ (with addition of1-2% triethylamine) gave the desired product.

4-(3-Methylpiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 8. The reaction was set upwith 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (1.0 g, 3.1 mmol),2-methylpiperazine (310 mg, 3.1 mmol), Pd₂(dba)₃ (56 mg, 0.061 mmol),2-(di-t-butylphosphino)biphenyl (73 mg, 0.25 mmol), NaO-tBu (930 mg,0.25 mmol), and toluene (7.0 mL) to obtain the desired amine as a tansolid (800 mg, 2.4 mmol, 76% yield). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=339.3; t_(R)=0.68 min.

4-(3-Methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 8. The reaction was set upwith 4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (1.0 g, 3.1mmol), 2-methylpiperazine (310 mg, 3.1 mmol, Pd₂(dba)₃ (56 mg, 0.061mmol), 2-(di-t-butylphosphino)biphenyl (73 mg, 0.25 mmol), NaO-tBu (930mg, 10 mmol), and toluene (7.0 mL). For the purification, 10% MeOH inCH₂Cl₂ with the addition of 2% triethylamine was used as a solventsystem to obtain the desired amide as a tan solid (130 mg, 0.38 mmol,12% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=340.3; t_(R)=0.96 min.

(R)-4-(3-Methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 8. The reaction was set upwith 4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (4.7 mmol),(R)-2-methylpiperazine (4.7 mmol), Pd₂(dba)₃ (0.12 mmol),2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), andtoluene (12 mL). For the purification, 10% MeOH in CH₂Cl₂ with theaddition of 1% triethylamine was used as a solvent system to obtain thedesired amine as a white solid (300 mg, 19% yield). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=340.2; t_(R)=1.56 min.

(S)-4-(3-Methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 8. The reaction was set upwith 4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (4.7 mmol),(S)-2-methylpiperazine (4.7 mmol), Pd₂(dba)₃ (0.12 mmol)2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), andtoluene (12 mL). For the purification, 10% MeOH in CH₂Cl₂ with theaddition of 1% triethylamine was used as a solvent system to obtain thedesired amine as a white solid (300 mg, 19% yield). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=340.2; t_(R)=1.40 min.

(R)-4-(3-Methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 8. The reaction was set upwith 4-bromo-N-(pyrimidin-4-yl)benzenesulfonamide (2.4 mmol),(R)-2-methylpiperazine (4.7 mmol), Pd(dba)₃ (0.12 mmol)2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), andtoluene (12 mL). For the purification, 10% MeOH in CH₂Cl₂ with theaddition of 1% triethylamine was used as a solvent system to obtain thedesired amine as a white solid. (900 mg, 100% yield). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=334.3; t_(R)=0.4 min.

(S)-4-(3-Methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 8. The reaction was set upwith 4-bromo-N-(pyrimidin-4-yl)benzenesulfonamide (2.4 mmol),(S)-2-methylpiperazine (4.7 mmol), Pd₂(dba)₃ (0.12 mmol),2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), andtoluene (12 mL). For the purification, 10% MeOH in CH₂Cl₂ with theaddition of 1% triethylamine was used as a solvent system to obtain thedesired amine as a white solid (300 mg, 38% yield). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=334.3; t_(R)=0.39 min.

General Procedure 9, Method A

A mixture of methylpiperazine (1.0 equivalent), carboxylic acid (1.0equivalent), BOP reagent (1.0 equivalent), triethylamine (1.0equivalent), and DMF (0.5-1.0 M of 4-methylpiperazine) was stirred at25° C. for 2-6 h. Purification via silica gel chromatography using 5%MeOH in CH₂Cl₂ gave the desired product.

General Procedure 9, Method B

A mixture of methylpiperazine (1.0 equivalent), carboxylic acid (1.0equivalent), HATU reagent (1.0 equivalent), sodium bicarbonate (1.5equivalents), and DMF/CH₂Cl₂-1/1 (0.5-1.0 M of 4-methylpiperazine) wasstirred at 25° C. for 19 h. Purification via silica gel chromatographyusing 10% MeOH in CH₂Cl₂ gave the desired product.

(S)-4-(4-(2-(5-fluoro-1H-indol-1-yl)acetyl)-3-methylpiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 9, method B. The reaction wasset up with(S)-4-(3-methylpiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (250mg, 0.74 mmol), 2-(5-fluoro-1H-indol-1-yl)acetic acid (143 mg, 0.74mmol), HATU reagent (281 mg, 0.74 mmol), sodium bicarbonate (93 mg, 1.11mmol), and DMF/CH₂Cl₂-1/1 (4.0 mL) to obtain the desired amide as awhite solid (200 mg, 0.39 mmol, 53% yield). ¹H NMR (400 MHz, DMSO-d6) 6(mixture of rotamers) 7.63-7.59 (m, 2H), 7.35 (s, 1H), 7.30 (dd, J=2.5,9.9 Hz, 2H), 7.21 (d, J=4.6 Hz, 1H), 7.00 (s, 1H), 6.95 (td, J=9.2, 3.9Hz, 2H), 6.76 (d, J=4.5 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 5.41-5.04 (m,2H), 4.52 (s, ½H), 4.38 (s, ½H), 4.21-4.05 (m, ½H), 3.93-3.82 (m, ½H),3.81-3.48 (m, 3H), 1.33 (s, 1.5; H), 1.14 (s, 1.5H). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=514.5; t_(R)=3.07 min.

4-(4-((R)-2-(1H-Indol-1-yl)propanoyl)-3-methylpiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 9, method A. The reaction wasset up with 0.1 mmol4-(3-methylpiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide, 0.1 mmol2-(5-fluoro-1H-indol-1-yl)acetic acid, 0.1 mmol BOP reagent, 0.1 mmoltriethylamine and DMF (300 μL). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=510.4; t_(R)=3.08 min.

4-(4-(3-(5-Chloro-1H-indol-1-yl)propanoyl)-3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 9, method A. The reaction wasset up with 0.1 mmol4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide,0.1 mmol 3-(5-chloro-1H-indol-1-yl)propanoic acid, 0.1 mmol BOP reagent,0.1 mmol triethylamine and DMF (300 μL). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=545.5; t_(R)=3.26 min.

(R)-4-(4-(2-(7-Chloro-1H-indol-1-yl)acetyl)-3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 9, method B. The reaction wasset up with(R)-4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(400 mg, 1.2 mmol), 2-(7-chloro-1H-indol-1-yl)acetic acid (250 mg, 0.15mmol), HATU reagent (390 mg, 0.15 mmol), sodium bicarbonate (151 mg, 1.8mmol), and DMF/CH₂Cl₂—1/1 (1.0 mL) to obtain the desired amide as awhite solid (230 mg, 36% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=531.0; t_(R)=3.21 min.

(S)-4-(4-(3-(5-Chloro-1H-indol-1-yl)propanoyl)-3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 9, method A. The reaction wasset up with 0.1 mmol(S)-4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide,0.15 mmol 3-(5-chloro-1H-indol-1-yl)propanoic acid, 0.15 mmol BOPreagent, 0.15 mmol triethylamine and DMF (300 μL). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=545.0; t_(R)=3.25 min.

4-(4-(2-(6-chloro-1H-indol-1-yl)acetyl)-3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 9, method A. The reaction wasset up with4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(35 mg, 0.10 mmol) 2-(6-chloro-1H-indol-1-yl)acetic acid (23 mg, 0.10mmol), BOP reagent (46 mg, 0.10 mmol), triethylamine (14 μL, 0.10 mmol),and DMF (300 μL). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=545.0; t_(R)=3.25 min.

4-(4-(3-(5-chloro-1H-indol-1-yl)propanoyl)-3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 9, method A. The reaction wasset up with4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide,(35 mg, 0.10 mmol) 3-(5-chloro-1H-indol-1-yl)propanoic acid (25 mg, 0.10mmol), BOP reagent (46 mg, 0.10 mmol), triethylamine (14 μL, 0.10 mmol),and DMF (300 μL). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=545.0; t_(R)=3.25 min.

(R)-4-(4-(3-(7-chloro-1H-indol-1-yl)propanoyl)-3-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 9, method A. The reaction wasset up with 0.1 mmol(R)-4-(3-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide,0.15 mmol 3-(7-chloro-1H-indol-1-yl)propanoic acid, 0.15 mmol BOPreagent, 0.15 mmol triethylamine and DMF (300 μL). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=539.5; t_(R)=2.89 min.

(S)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)acetyl)-3-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 9, method A. The reaction wasset up with 0.1 mmol(S)-4-(3-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide,0.15 mmol 2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)acetic acid, 0.15mmol BOP reagent, 0.15 mmol triethylamine and DMF (300 μL). LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=541.5;t_(R)=2.96 min.

Example 3(R)-tert-Butyl-3-(O-tert-butyldiphenylsilane)methyl-piperazine-1-carboxylate

A mixture of (R)-tert-butyl-3-(hydroxymethyl)piperazine-1-carboxylate (1g, 4.62 mmol) and imidazole (0.629 g, 9.24 mmol) was dissolved in CH₂Cl₂(10 mL). Tert-butylchlorodiphenylsilane (1.18 mL, 5.08 mmol) was addeddropwise over 10 minutes. Upon completion of addition, the mixture wasstirred at RT for 3 hours. The reaction mixture was diluted with 50 mLof CH₂Cl₂ and washed with saturated aqueous sodium bicarbonate (3×20mL), brine (2×20 mL), dried over magnesium sulfate, and concentrated.Purification via silica gel chromatography using 2-10% methanol inCH₂Cl₂ gave(R)-tert-butyl-3-(O-tert-butyldiphenylsilane)methyl-piperazine-1-carboxylateas a white solid (1.7 g, 81%). ¹H NMR (400 MHz, DMSO-d6) δ 7.63-7.61 (m,5H), 7.48-7.45 (m, 5H), 4.13-3.44 (m, 5H), 2.80 (d, J=11.8 Hz, 2H), 2.66(d, J=5.7 Hz, 2H), 1.40 (s, 9H), 1.01 (s, 9H). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=455.5; t_(R)=3.05 min.

(R)-2-(O-tert-butyldiphenylsilane)methyl-piperazine dihydrochloride

Under N₂ atmosphere, a solution of(R)-tert-butyl-3-(O-tert-butyldiphenylsilane)methyl-piperazine-1-carboxylate(1.7 g, 3.74 mmol) in a solution of HCl in 1,4-dioxane (4 M, 60 mL) wasstirred at RT for 16 h. The formed precipitate was filtered off andwashed with 1,4-dioxane (20 mL) to give2-(O-tert-butyldiphenylsilane)methyl-piparizine dihydrochloride (1.4 g,88%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=355.5; t_(R)=2.42 min.

General Procedure 10

A mixture of 4-bromobenzenesulfonamide (1 equivalent), piperazine (1-10equivalents), Pd₂(dba)₃ (0.02-0.075 equivalents),2-(di-t-butylphosphino) biphenyl (0.08-0.2 equivalents), NaO-tBu (2-6equivalents) and toluene (0.1-0.4 M of 4-bromobenzenesulfonamide) washeated at 80° C. for 1-6 h. Purification via silica gel chromatographyusing 10% MeOH in CH₂Cl₂ (with addition of 1-2% triethylamine) gave thedesired product.

4-((R)-2-O-tert-butyldiphenylsilane)methyl-piperazine-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 10. A mixture of(R)-2-(O-tert-butyldiphenylsilane)methyl-piperazine-dihydrochloride (1g, 2.33 mmol), 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (0.74 g, 2.33mmol), Pd₂(dba)₃ (426 mg, 0.466 mmol),4,5-bis(diphenyl)phosphino-9,9-dimethyl xanthene (270 mg, 0.466 mmol),NaO-tBu (1.34 g, 13.98 mmol) was purged with N₂ (3 times). 1,4-Dioxane(20 mL) was added to the above mixture under N₂. The reaction wasstirred at 80° C. for 1 h, cooled and filtered over Celite. The filtratewas concentrated. Purification via silica gel chromatography using 2-10%methanol in CH₂Cl₂ gave4-((R)-3-(O-tert-butyldiphenylsilane)methyl-piperazine-N-(thiazol-2-yl)benzenesulfonamideas a white solid (0.85 g, 64%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=593.4; t_(R)=2.97 min.

General Procedure 11

To the carboxylic acid (1.2 equivalent, 0.17 mmol) and NaHCO₃ (2equivalent, 0.22 mmol) was added HATU (1.2 equivalent, 0.17 mmol) in DMF(0.15-0.25M, 0.25 mL). A solution of the amine (1 equivalent, 0.11 mmol)in DMF (0.15-0.25M, 0.25 mL) was then added and the reaction mixture wasstirred at RT for 19 h. The reaction mixture was diluted with 5 mL ofethyl acetate and washed with water (3×5 mL), saturated aqueous sodiumbicarbonate (3×5 mL) and with brine (2×5 mL). The organic layer wasdried over magnesium sulfate, filtered, and concentrated to giveO-tert-butyldiphenylsilane protected benzenesulfonamide. The crudematerial was dissolved in THF (2 mL) and cooled to 0° C. To this wasadded a solution of 1 M TBAF in THF (0.2 mL. 0.2 mmol). The reactionmixture was stirred at RT for 4 h, concentrated and purified via silicagel chromatography using 5% methanol in CH₂Cl₂ to give the desiredproduct.

(S)-2-(2,3-Dichlorophenoxy)-1-((R)-2-(hydroxymethyl)-4-(4-N-(thiazol-2-yl)benzenesulfonamide)piperazin-1-yl)propan-1-one

Prepared using general procedure 11. A solution of(S)-2-(2,3-dichlorophenoxy) propanoic acid (285.3 mg, 1.21 mmol) andHATU (456 mg, 1.21 mmol) in DMF (10 mL) was stirred under an N₂atmosphere at 0° C. for 1 h. To this mixture,4-((R)-2-O-tert-butyldiphenylsilane)methyl-piperazine-N-(thiazol-2-yl)benzenesulfonamide(600 mg, 1.0 mmol) and NaHCO₃ (201 mg, 2.4 mmol) were added under an N₂atmosphere at RT, and the reaction was stirred for 16 h. The reactionmixture was diluted with ethyl acetate (30 mL), washed with water (3×50mL), saturated aqueous sodium bicarbonate (3×50 mL) and with brine (2×50mL). The organic layer was dried over magnesium sulfate, filtered, andconcentrated. Purification via silica gel chromatography using 20-100%ethyl acetate in hexane gave crude(S)-2-(2,3-dichlorophenoxy)-1-(R)-2-(O-tert-butyldiphenylsilane)-4-(4-N-(thiazol-2-yl)benzenesulfonamide)piperazin-1-yl)propan-1-one(2.0 g). The crude material was dissolved in THF (5 mL) and cooled to 0°C. To this was added a solution of 1 M TBAF in THF (5 mL, 5 mmol). Thereaction mixture was stirred at RT for 4 h, concentrated and purifiedvia silica gel chromatography using 5% methanol in CH₂Cl₂ to give(S)-2-(2,3-Dichlorophenoxy)-1-(R)-2-(hydroxymethyl)-4-(4-N-(thiazol-2-yl)benzenesulfonamide)piperazin-1-yl)propan-1-one(200 mg, 34%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=571.2; t_(R)=2.95 min. ¹H NMR (400 MHz, DMSO-d6) δ 7.61 (d,J=9.0 Hz, 2H), 7.28-7.18 (m, 3H), 7.01-6.95 (m, 2H), 6.88-6.87 (m, 1H),6.78 (d, J=4.5 Hz, 1H), 5.54-4.93 (m, 2H), 4.39-3.49 (m, 6H), 3.02-2.86(m, 2H), 1.52 (d, J=6.4 Hz, 3H).

4-((R)-4-(R)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)-3-(hydroxymethyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 11. A solution of(R)-2-(6-chloro-3,4-dihydroquinolin-1-(2H)-yl)propanoic acid (483 mg,2.01 mmol) and HATU (763 mg, 2.01 mmol) in DMF (5 mL) was stirred underan N₂ atmosphere at 0° C. for 1 h. To this mixture,4-((R)-2-O-tert-butyldiphenylsilane)methyl-piperazine-N-(thiazol-2-yl)benzenesulfonamide(1000 mg, 1.68 mmol) and NaHCO₃ (282 mg, 3.36 mmol) were added under anN₂ atmosphere at RT, and the reaction was stirred for 16 hr. Thereaction mixture was diluted with ethyl acetate (30 mL), washed withwater (3×50 mL), saturated aqueous sodium bicarbonate (3×50 mL) and withbrine (2×50 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated. Purification via silica gel chromatographyusing 20-100% ethyl acetate in hexane gave crude4-((R)-4-(R)-2-(6-chloro-3,4-dihyroquinolin-1(2H)-yl)propanoyl)-3-(O-tert-butyldiphenylsilane)methyl-piperizine)-N-(thiazol-2-yl)benzenesulfonamide(1.0 g, 74%). The crude material was dissolved in THF (5 mL) and cooledto 0° C. To this was added a solution of 1 M TBAF in THF (2 mL, 2 mmol).The reaction mixture was stirred at RT for 4 h, concentrated andpurified via silica gel chromatography using 5% methanol in CH₂Cl₂ togive4-((R)-4-(R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)-3-(hydroxymethyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(400 mg, 41% over 2 steps). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=576.13; t_(R)=3.14 min. ¹H NMR (400 MHz, DMSO-d6) δ7.58 (d, J=11.5 Hz, 2H), 7.21 (d, J=7.8 Hz, 1H), 7.03-6.92 (m, 4H),6.78-6.76 (m, 2H), 5.00-4.79 (m, 2H), 4.43 (d, J=2.9 Hz, 1H), 4.06-3.38(m, 5H), 3.20-2.59 (m, 6H), 1.87-1.72 (m, 2H), 1.24 (s, 3H).

4-((R)-4-(S)-2-(6-Chloro-1H-indol-1-yl)propanoyl)-3-(hydroxymethyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 11. A solution of(S)-2-(6-chloro-1H-indol-1-yl) propanoic acid (207.3 mg, 0.93 mmol) andHATU (353.9 mg, 0.93 mmol) in DMF (5 mL) was stirred under an N₂atmosphere at 0° C. for 1 h. To this mixture,4-((R)-2-O-tert-butyldiphenylsilane)methyl-piperazine-N-(thiazol-2-yl)benzenesulfonamide(460 mg, 0.77 mmol) and NaHCO₃ (141 mg, 1.68 mmol) were added under anN₂ atmosphere at RT, and the reaction was stirred for 16 h. The reactionmixture was diluted with ethyl acetate (30 mL), washed with water (3×50mL), saturated aqueous sodium bicarbonate (3×50 mL) and with brine (2×50mL). The organic layer was dried over magnesium sulfate, filtered, andconcentrated. Purification via silica gel chromatography using 20-100%ethyl acetate in hexane gave crude4-((R)-4-(S)-2-(6-chloro-1H-indol-1-yl)propanoyl)-3-(O-tert-butyldiphenylsilane)methyl-piperazine)-N-(thiazol-2-yl)benzenesulfonamide(0.32 g, 51%). The crude material was dissolved in THF (5 mL) and cooledto 0° C. To this was added a solution of 1 M TBAF in THF (1 mL, 1 mmol).The reaction mixture was stirred at RT for 4 h, concentrated andpurified via silica gel chromatography using 5% methanol in CH₂Cl₂ togive4-((R)-4-((S)-2-(6-chloro-1H-indol-1-yl)propanoyl)-3-(hydroxymethyl)piperazin-1-yl)-N-(thiazol-2-yl)benzene-sulfonamide(120 mg, 50% over 2 steps). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=560.2; t_(R)=3.02 min. ¹H NMR (400 MHz, DMSO-d6) δ7.66 (s, 1H), 7.57 (t, J=9.7 Hz, 3H), 7.44-7.39 (m, 1H), 7.21 (d, J=4.6Hz, 1H), 7.07-7.03 (m, 1H), 6.93 (dd, J=16.4, 9.0 Hz, 2H), 6.76 (d,J=4.6 Hz, 1H), 6.51 (t, J=3.4 Hz, 1H), 5.85-5.80 (m, 1H), 5.16 (t, J=5.5Hz, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.50 (s, 1H), 4.31 (d, J=14.4 Hz, 1H),4.05-3.37 (m, 3H), 3.03-2.90 (m, 2H), 1.57-1.51 (m, 3H).

Example 4 4-Benzyl-1-phenylpiperazin-2-one

To a 25 mL microwave vessel was added 4-bromobenzene (6.1 g, 39.0 mmol),4-benzylpiperazin-2-one (5.0 g, 36.3 mmol), potassium carbonate (3.6 g,26.3 mmol), and copper(I) iodide (500 mg, 2.6 mmol). The reaction vesselwas sealed and purged with nitrogen. Anhydrous NMP (8.0 mL) was addedvia syringe. The vessel was heated via microwave at 220° C. for 40minutes. The mixture was filtered through a bed of celite followed byCH₂Cl₂ (20 mL). The filtrate was purified via silica gel chromatographyusing 2% MeOH in CH₂Cl₂ to obtain the desired piperazinone as a whitesolid (3.4 g, 12.7 mmol, 50% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.24(m, 10H), 3.69 (t, J=5.4 Hz, 1H), 3.63 (s, 1H), 3.40-3.31 (m, 2H), 2.84(s, 1H), 2.81 (t, J=5.2 Hz, 1H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=267.3; t_(R)=1.63 min.

1-Phenylpiperazin-2-one

A mixture of 4-benzyl-1-phenylpiperazin-2-one (13.0 g, 48.8 mmol), 10%palladium on carbon (700 mg), and acetic acid (150 mL) was stirred underhydrogen at atmospheric pressure for 3 hours. The reaction was purgedwith nitrogen and filtered through a bed of celite. The filtrate wasconcentrated and the residue was purified via silica gel chromatographyusing 10% MeOH in CH₂Cl₂ to obtain the desired piperazinone as a whitesolid (8.3 g, 146.8 mmol, 96% yield). ¹H NMR (400 MHz, CDCl₃) δ7.43-7.38 (m, 2H), 7.30-7.26 (m, 3H), 3.70-3.67 (m, 4H), 3.35 (s, 1H),3.22 (t, J=5.5 Hz, 2H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=177.2; t_(R)=0.44 min.

1-Phenyl-4-(2,2,2-trifluoroacetyl)piperazin-2-one

To a stirring solution of 1-phenylpiperazin-2-one (1.3 g, 7.1 mmol),triethylamine (0.72 g, 7.1 mmol), and CH₂Cl₂ (20 mL), at −78° C., wasadded trifluoroacetic anhydride (1.48 g, 7.1 mmol) dropwise over 10minutes. The mixture was then allowed to warm to 25° C. over 30 minutes.The reaction mixture was partitioned between CH₂Cl₂ and water. Theorganic portion was evaporated and purified via silica gelchromatography using 30% EtOAc in hexanes to obtain the desired amide asa white solid (1.2 g, 4.4 mmol, 62% yield). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=272.8; t_(R)=2.48 min. ¹H NMR (400MHz, CDCl₃) δ 7.51-7.40 (m, 2H), 7.39-7.21 (m, 3H), 4.45 (s, 2H),4.11-3.98 (m, 2H), 3.86-3.81 (m, 2H).

4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonylchloride

A stirring solution of 1-phenyl-4-(2,2,2-trifluoroacetyl)piperazin-2-one(1.2 g, 4.4 mmol) and chlorosulfonic acid (3.0 mL), under N₂, was heatedat 80° C. for 40 minutes. The mixture was cooled to 0° C. and pouredinto ice-water (150 mL) followed by the addition of EtOAc (300 mL). Theorganic portion was evaporated and purified via silica gelchromatography using 50% EtOAc in hexanes to obtain the desired sulfonylchloride as a clear oil (900 mg, 2.4 mmol, 55% yield). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=370.8; t_(R)=3.02 min.¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, 2H), 7.65 (d, 2H), 4.51 (s, 2H), 4.11(t, 2H), 3.93 (t, 2H).

General Procedure 12, Method A

Under an N₂ atmosphere, a mixture of the sulfonyl chloride (1 mmol) andaminoheterocycle (1 mmol), and pyridine (1.0 mL) was stirred at RT for19 h. The crude product was purified via silica gel chromatography usingMeOH in CH₂Cl₂.

General Procedure 12, Method B

Under an N₂ atmosphere, a mixture of the sulfonyl chloride (1 mmol) andaminoheterocycle (1 mmol), and DABCO (1 mmol) in acetonitrile (5.0 mL)was stirred at RT for 19 h. The crude product was purified via silicagel chromatography using MeOH in CH₂Cl₂.

4-(2-Oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 12, method A. The reactionwas set up with 2-aminothiazole (2.4 g, 24.2 mmol), anhydrous pyridine(10 mL), and4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonylchloride (9.0 g, 24.2 mmol). The dark oil was purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ followed by a second purificationon silica gel using 80% EtOAc in hexanes to obtain the desiredsulfonamide as a white solid (5.1 g, 11.7 mmol, 48% yield). LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=435.2;t_(R)=2.35 min.

4-(2-Oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 12, method A. The reactionwas set up with 1,2,4-Thiadiazol-5-ylamine hydrochloride (0.56 g, 4.0mmol), anhydrous pyridine (3.5 mL), and4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonylchloride (1.5 g, 4.0 mmol). The dark oil was purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ followed by a second purificationon silica gel using 80% EtOAc in hexanes to obtain the desiredsulfonamide as a white solid (0.73 g, 1.92 mmol, 48% yield). LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=436.1;t_(R)=2.27 min.

4-(2-Oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 12, method B. The reactionwas set up with 4-aminopyrimidine (0.26 g, 2.16 mmol), anhydrousacetonitrile (10 mL), DABCO (0.24 gm, 2.16 mmol) and4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonylchloride (0.80 g, 2.16 mmol). The dark oil was purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ followed by a second purificationon silica gel using 80% methanol in dichloromethane to obtain thedesired sulfonamide as a white solid (0.43 g, 0.93 mmol, 47% yield).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=439.3;t_(R)=2.3 min

General Procedure 13

To a stirring solution of sodium hydroxide (10 equivalents, 10 mmol),and H₂O (5.0 mL), at 0° C., was added the trifluoromethylacetyl amine (1equivalent, 1 mmol) portionwise over 10 minutes. The mixture was stirredat ambient temperature for 30 minutes. The solution was cooled to 0° C.followed by the addition of 1.0 N HCl aqueous solution (10 equivalents,10 mmol). The product was purified by azeotroping with MeOH ortitration.

4-(2-Oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

To a stirring solution of sodium hydroxide (1.38 g, 34.5 mmol), and H₂O(5.0 mL), at 0° C., was added4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(5.0 g, 11.5 mmol) portionwise over 10 minutes. The mixture was stirredat ambient temperature for 30 minutes. The solution was cooled to 0° C.followed by the addition of 1.0 N HCl aqueous solution (34.5 mL, 34.5mmol). The light yellow solution was azeotroped with MeOH (4×100 mL) at<30° C. The obtained solid was suspended in 50% MeOH in CH₂Cl₂ (200 mL)and stirred for 5 minutes. The mixture was filtered and the filtrate wasevaporated to give the desired amine as light yellow solid (2.5 g, 7.4mmol, 64% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=339.3; t_(R)=0.51 min.

4-(2-Oxopiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Prepared using general procedure 13. To a stirring solution of sodiumhydroxide (0.67 g, 16.8 mmol), and H₂O (5.0 mL), at 0° C., was added4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(1,2,4-thiazol-2-yl)benzenesulfonamide(0.73 g, 1.68 mmol) portionwise over 10 minutes. The mixture was stirredat ambient temperature for 30 minutes. The solution was cooled to 0° C.followed by the addition of 1.0 N HCl aqueous solution (16.8 mL, 16.8mmol). The light yellow solution was azeotroped with MeOH (4×100 mL) at<30° C. The obtained solid was suspended in 50% MeOH in CH₂Cl₂ (200 mL)and stirred for 5 minutes. The mixture was filtered and the filtrate wasevaporated to give the desired amine as light yellow solid (1.15 g, 1.68mmol, 100% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=340.1; t_(R)=0.44 min.

4-(2-Oxopiperazin-1-yl)-N-(pyrimidin-4-yl)benzene-sulfonamide

Prepared using general procedure 13. To a stirring solution of sodiumhydroxide (1.0M in H₂O, 10 mL, 10 mmol), at 0° C., was added4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide(0.45 g, 1.01 mmol) portionwise over 10 minutes. The mixture was stirredat ambient temperature for 30 minutes. The solution was cooled to 0° C.followed by the addition of 1.0 N HCl aqueous solution (10 mL, 10 mmol).The light yellow solution was azeotroped with MeOH (4×100 mL) at <30° C.The obtained solid was suspended in 50% MeOH in CH₂Cl₂ (200 mL) andstirred for 5 minutes. The mixture was filtered and the filtrate wasevaporated to give the desired amine as light yellow solid (1.15 g,quantitative yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=334.1; t_(R)=0.44 min.

General Procedure 14, Method A

A mixture of piperazinone (1.0 equivalent), carboxylic acid (1.0equivalent), HATU reagent (2.0 equivalent), sodium carbonate (3.0equivalents), and DMF/CH₂Cl₂ (0.5-1.0 M in reference to piperazinone)was stirred at 25° C. for 19 h. Purification via silica gelchromatography using 5% MeOH in CH₂Cl₂ gave the desired product.

General Procedure 14, Method B

A mixture of piperazinone (1.5 equivalent), carboxylic acid (1.0equivalent), HATU reagent (2.0 equivalent), sodium carbonate (2.0equivalents), and DMF (1.3 M in reference to piperazinone) was stirredat 25° C. for 2-6 h. Purification via Gilson HPLC gave the desiredproduct.

4-(2-Oxo-4-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method A. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (100 mg, 0.29mmol), 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (71 mg, 0.29mmol), HATU reagent (220 mg, 0.58 mmol), sodium bicarbonate (74 mg, 0.87mmol), and DMF/CH₂Cl₂—1/1 (0.50 mL) to obtain the desired amide as awhite solid (55 mg, 0.10 mmol, 34% yield). ¹H NMR (400 MHz, DMSO-d6) δ12.78 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.3 Hz,1H), 7.58 (dd, J=5.1, 8.4 Hz, 2H), 7.52-7.48 (m, 1H), 7.32-7.27 (m, 2H),6.85 (d, J=4.6 Hz, 1H), 6.61 (d, J=2.9 Hz, 1H), 5.40 (d, J=9.8 Hz, 2H),4.49 (s, 1H), 4.22 (s, 1H), 4.01 (s, 2H), 3.81 (s, 2H). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=564.4; t_(R)=3.17 min.

1-Methyl 2-(4-fluoro-1H-indol-1-yl) propanoate

To a cooled (0-5° C.) solution of 2-(4-fluoro-1H-indol-1-yl)propanoicacid (19.0 g, 92 mmol) in methanol (250 mL) was added, dropwise, thionylchloride (15 mL, 207 mmol). The resulting solution was stirred overnightat room temperature. The mixture was evaporated to dryness and theresidue was dissolved in ethyl acetate (0.5 L). This solution was washedwith water (2×200 mL), brine (200 mL), dried over sodium sulfate,filtered, and evaporated to dryness to give the desired methyl ester asbrownish oil (26.0 g, 92 mmol, 100% yield). ¹H-NMR (300 MHz, CDCl₃) δ7.24-7.23 (m, 1H), 7.18-7.04 (m, 2H), 6.82-6.78 (m, 1H), 6.65-6.63 (m,1H), 5.17 (q, J=7.3 Hz, 1H), 3.72 (s, 3H), 1.82 (d, J=7.3 Hz, 3H).

Methyl 2-(4-fluoro-1H-indol-1-yl)-2-methylpropanoate

1-Methyl 2-(4-fluoro-1H-indol-1-yl) propanoate (20.6 g, 93 mmol) wasdissolved in anhydrous THF (100 mL) under a nitrogen atmosphere. Thissolution was cooled to −78° C. and a solution of 1.8 M lithiumdiisopropylamide in THF/hexanes/ethylbenzene (commercial grade, 60 mL,108 mmol) was slowly added via syringe. During the addition, theinternal temperature was kept below −60° C. The mixture was stirred at−78° C. for 1 h. Methyl iodide (11 mL, 177 mmol) was added via syringe.After 15 minutes at −78° C. the dry ice/acetone bath was removed and thereaction mixture was left warming up to room temperature. Ethyl acetate(0.5 L) was added and the solution was washed with water (3×200 mL), 1Naq. HCl (2×200 mL), water (2×200 mL), brine (3×100 mL), and dried oversodium sulfate. The solution was evaporated to dryness at 50° C. underreduced pressure to yield the desired ester (21.3 g, 90 mmol, 97%yield). ¹H-NMR (300 MHz, CDCl₃): δ 7.10-7.04 (m, 1H), 6.95-6.93 (m, 2H),6.82-6.75 (m, 1H), 6.62-6.60 (m, 1H), 3.68 (s, 3H), 1.89 (s, 6H).

2-(4-Fluoro-1H-indol-1-yl)-2-methylpropanoic acid

A mixture of 1-Methyl 2-(4-fluoro-1H-indol-1-yl)propanoate (21.3 g, 91mmol), 1 N aq. NaOH (150 mL), and methanol (150 mL) was heated to 75° C.overnight. The volatiles were removed by evaporation under reducedpressure at 50° C. and ethyl acetate (250 mL) and water (200 mL) wereadded to the residue. The layers were separated and the aqueous layerwas acidified with concentrated HCl to pH<1. The acidified layer wasextracted with ethyl acetate (1×200 mL, 1×50 mL) and the combinedextracts were washed with brine (100 mL), dried over sodium sulfate,filtered, and evaporated to dryness under reduced pressure at 50° C. toobtain the desired acid as a yellow oil (16.8 g, 76 mmol, 84% yield).¹H-NMR (300 MHz, CDCl₃): δ 7.12-6.99 (m, 2H), 6.83-6.77 (m, 2H),6.63-6.62 (m 1H), 1.92 (s, 6H).

Methyl 2-(6-trifluoromethyl-1H-indol-1-yl) propanoate

To a solution of 6-trifluoromethyl indole (1.33 g, 7.18 mmol) in DMSO (7mL) was added portionwise potassium hydroxide (0.75 mL, 13.37 mmol). Theresulting solution was stirred at room temperature for 15 minutes. Tothis was added methyl-2-bromo propionate (3.6 mL, 32.29 mmol) in asingle portion. The reaction mixture was stirred at room temperature for16 hrs. The solution was cooled to 0° C. and quenched with water (20mL). The mixture was extracted with CH₂Cl₂ (50 mL). This solution waswashed with a saturated solution of ammonium chloride (2×20 mL), brine(200 mL), dried over sodium sulfate, filtered, and concentrated.Purification via silica gel chromatography using 15-40% CH₂Cl₂ inhexanes gave the methyl ester as a clear oil (0.89 g, 3.23 mmol, 45%yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA), m/z: M+1obs=272.0; t_(R)=3.56 min. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J=8.3 Hz,1H), 7.62 (s, 1H), 7.45 (d, J=3.3 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.67(d, J=3.2 Hz, 1H), 5.26-5.20 (m, 1H), 3.76 (s, 3H), 1.88 (d, J=7.3 Hz,3H).

Methyl 2-(6-trifluoromethyl-1H-indol-1-yl)-2-methylpropanoate

Methyl 2-(6-trifluoromethyl-1H-indol-1-yl) propanoate (0.89 g, 3.28mmol) was dissolved in anhydrous THF (7 mL) under a nitrogen atmosphere.This solution was cooled to −78° C. and a solution of 2M lithiumdiisopropylamide in THF/heptane/ethylbenzene (1.97 mL, 3.94 mmol) wasslowly added via syringe. During the addition, the internal temperaturewas kept below −60° C. The mixture was stirred at −78° C. for 1 h.Methyl iodide (0.39 mL, 6.23 mmol) was added via syringe. After 15minutes at −78° C. the dry ice/acetone bath was removed and the reactionmixture was left to warm up to room temperature. Ethyl acetate (0.5 L)was added and the solution was washed with water (3×20 mL), 1N aq. HCl(2×20 mL), water (2×20 mL), brine (3×10 mL), and dried over sodiumsulfate. The solution was evaporated to dryness at 50° C. under reducedpressure to give the desired ester (0.84 g, 2.95 mmol, 90% yield). ¹HNMR (400 MHz, CDCl₃) δ 7.73 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.45 (d,J=3.3 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.67 (d, J=3.2 Hz, 1H), 3.76 (s,3H), 1.88 (s, 6H).

2-(6-Trifluoromethyl-1H-indol-1-yl)-2-methylpropanoic acid

A mixture of methyl2-(6-trifluoromethyl-1H-indol-1-yl)-2-methylpropanoate (1.48 g, 5.18mmol), 1 N aq. NaOH (9 mL), and methanol:THF (1:1, 18 mL) was heated to75° C. overnight. The volatiles were removed by evaporation underreduced pressure at 50° C. and to the residue was added ethyl acetate(50 mL) and water (15 mL). The layers were separated and the aqueouslayer was acidified with concentrated HCl to pH<1. The acidified layerwas extracted with ethyl acetate (3×20 mL), and the combined extractswere washed with brine (20 mL), and dried over sodium sulfate. Thesolution was concentrated and the residue was purified via silica gelchromatography using 0-5% methanol in CH₂Cl₂ to obtain the desired acidas a clear oil (0.58 g, 2.12 mmol, 41% yield). ¹H NMR (400 MHz, CDCl₃) δ7.65 (d, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.29 (d, J=19.0 Hz, 1H), 6.51(s, 1H), 1.92 (d, J=39.0 Hz, 6H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA), m/z: M+1 obs=272.2; t_(R)=3.61 min.

2-(5-Chloro-2-methyl-1H-indol-1-yl)propanoic acid

To a 0° C. solution of 5-chloro-2-methyl-indole (0.100 g, 0.6 mmol) inDMSO (6 mL) was added portionwise potassium hydroxide (0.33 g, 6 mmol).The resulting solution was stirred at room temperature for 15 minutes.To this was added methyl-2-bromo propionate (0.1 mL, 0.9 mmol) in asingle portion. The reaction mixture was stirred at room temperature for16 h. The solution was cooled to 0° C. and quenched with water (20 mL).The mixture was extracted with CH₂Cl₂ (50 mL). This solution was washedwith a saturated solution of ammonium chloride (2×20 mL), brine (200mL), and dried over sodium sulfate. The solution was concentrated andthe residue was purified via silica gel chromatography using 15-40%CH₂Cl₂ in hexanes to obtain the methyl ester as a clear oil (0.05 g,0.21 mmol, 35% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA), m/z: M+1 obs=238; t_(R)=3.03 min.

(R)-Methyl 2-hydroxy-3-methylbutanoate

To a solution of (R)-2-hydroxy-3-methylbutanoic acid (5.0 gm, 42.2 mmol)in methanol was added a solution of TMS.CH₂N₂ (2M) in hexane (65 mL), at0° C., over 20 min. The reaction mixture was stirred at 0° C. for 1 h.The reaction was concentrated with a bath temperature of 20° C. andvacuum greater than 50 mm Hg. Purification via silica gel chromatographyusing 2-100% EtOAc in hexanes gave the ester as a yellow oil (438 mg,12.7 mmol, 30% yield). ¹H NMR (400 MHz, DMSO-d6) δ 5.30 (d, J=5.1 Hz,1H), 3.81 (t, J=0.8 Hz, 1H), 3.63 (s, 3H), 1.94-1.86 (m, 1H), 0.88-0.82(m, 6H).

(R)-1-(Methoxycarbonyl)-2-methylpropyl-trifluoromethane sulfonate

Triflic anhydride (0.58 mL, 3.31 mmol) was slowly added to a stirringsolution of (R)-methyl 2-hydroxy-3-methylbutanoate (0.43 g, 3.31 mmol)in CH₂Cl₂ (5 mL), under N₂, at −30° C. The reaction mixture was stirredfor 10 minutes followed by the addition of 2,6-lutidine (0.38 mL, 3.31mmol). The reaction was stirred at room temperature for 16 hours. Thereaction mixture was filtered over a small silica pad and washed withethyl acetate and hexane (1:1, 10 mL). Concentration with a bathtemperature of 20° C. and vacuum greater than 50 mm Hg gave the desiredtriflate as a yellow oil (0.78 g, 2.98 mmol, 90% yield). ¹H NMR (400MHz, DMSO-d6) δ 5.13 (s, 1H), 3.81 (s, 3H), 2.35-2.20 (m, 1H), 1.05-0.84(m, 6H).

(S)-Ethyl 2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoate

(R)-1-(Methoxycarbonyl)-2-methylpropyl-trifluoromethane sulfonate (200mg, 0.75 mmol) in 1,2-dichloroethane (1 mL), was slowly added to astirring solution of 6-chloro-1,2,3,4-tetrahydroquinoline (100 mg, 0.60mmol), 2,6-lutidine (0.105 mL, 9.09 mmol), and 1,2-dichloroethane (5mL), under N₂, at 25° C. The reaction was heated at 70° C. for 19 hours.The mixture was washed with H₂O and extracted twice with CH₂Cl₂. Theorganic layer was dried over MgSO₄, filtered, and concentrated.Purification via silica gel chromatography using 0-20% EtOAc in hexanesgave the desired ester as a yellow oil (30 mg, 0.11 mmol, 15% yield).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=282.2;t_(R)=4.04 min.

(S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoic acid

At 0° C., an aqueous 2.0 M KOH solution (14 mL, 28 mmol) was added to astirring solution of(S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoic acid (80mg, 0.28 mmol) in MeOH (2 mL). The reaction was allowed to warm up to RTand left stirring overnight. Due to the instability of the final productas a solid, the solution containing(S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoic acid wasused for the next step without further work up. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=268.4; t_(R)=3.57 min.

(S)-Methyl 2-hydroxy-4-methylpentanoate

To a solution of (S)-2-hydroxy-4-methylpentanoic acid (3.0 g, 22.7 mmol)in methanol was added TMS.CH₂N₂ (2M in hexanes, 34 mL, 17 mmol)dropwise, at 0° C., over 20 min. The reaction mixture was stirred at 0°C. for 1 h. The solution was concentrated using a bath temperature of20° C. and vacuum greater than 50 mm Hg. Purification via silica gelchromatography using 2-100% EtOAc in hexanes gave the ester as a yellowoil (2.14 g, 14.5 mmol, 64% yield). ¹H NMR (400 MHz, DMSO-d6) δ 5.13 (s,1H), 4.1-4.0 (m, 1H), 3.81 (s, 3H), 1.6-1.5 (m, 1H), 2.35-2.20 (m, 2H),1.05-0.84 (m, 6H).

(S)-1-(Methoxycarbonyl)-3-methylbutyl-trifluoromethane sulfonate

Under an N₂ atmosphere, at −30° C., triflic anhydride (2.69 mL, 16.0mmol) was slowly added to a stirring solution of (R)-methyl2-hydroxy-4-methylpentanoate (2.11 g, 14.5 mmol) in CH₂Cl₂ (33 mL).After stirring the reaction mixture for 10 minutes, 2,6-lutidine (1.94mL, 16.7 mmol) was added. The reaction was stirred at room temperaturefor 16 h. The reaction mixture was filtered over a small silica pad andwashed with ethyl acetate and hexane (1:4, 400 mL). The solution wasconcentrated using a bath temperature of 20° C. and vacuum greater than50 mm Hg to obtain the desired triflate as a yellow oil (4.03 g, 16.7mmol, 100% yield). ¹H NMR (400 MHz, DMSO-d6) δ 4.08-4.01 (m, 1H), 3.82(s, 3H), 2.52-2.50 (m, 2H), 1.99 (s, 1H), 1.19-0.90 (m, 6H).

(R)-Ethyl 2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-methylpentanoate

Under an N₂ atmosphere, at 25° C.,(R)-1-(methoxycarbonyl)-2-methylpropyl-trifluoromethane sulfonate (300mg, 1.08 mmol) in 1,2-dichloroethane (1 mL) was slowly added to astirring solution of 6-chloro-1,2,3,4-tetrahydroquinoline (164 mg, 0.98mmol) and 2,6-lutidine (0.132 mL, 1.13 mmol) in 1,2-dichloroethane (1.4mL). The reaction was then heated at 70° C. for 19 hours. The mixturewas washed with H₂O and extracted twice with CH₂Cl₂. The organic layerwas dried over MgSO₄, filtered, and concentrated. Purification viasilica gel chromatography using 0-20% EtOAc in hexanes gave the ester asa yellow oil (295 mg, 0.98 mmol, 100% yield). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=296.5; t_(R)=4.25 min.

(R)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-methylpentanoic acid

KOH (2.0 M in H₂O, 0.34 mL, 0.68 mmol) was added to a 0° C., stirringsolution of (R)-ethyl2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-methylpentanoate (50 mg,0.17 mmol) in MeOH (0.32 mL). The reaction was allowed to warm to RT andstirred overnight. Due to the instability of the final product as asolid, the solution containing(5)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoic acid wasused for the next step without further work up. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=282.3; t_(R)=3.72 min.

4-(4-(2-(4-Fluoro-1H-indol-1-yl)-2-methylpropanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method A. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (100 mg, 0.29mmol), 2-(6-fluoro-1H-indol-1-yl)-2-methylpropanoic acid (66 mg, 0.29mmol), HATU reagent (220 mg, 0.58 mmol), sodium bicarbonate (74 mg, 0.87mmol), and DMF/CH₂Cl₂-1/1 (0.50 mL) to obtain the desired amide as awhite solid (50 mg, 0.10 mmol, 32% yield). ¹H NMR (400 MHz, DMSO-d6) δ12.76 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.66 (s, 1H), 7.27-6.91 (m, 5H),6.90-6.82 (m, 2H), 6.68 (d, J=3.0 Hz, 1H), 4.23 (s, 1H), 3.87 (bs, 1H),3.57 (bs, 1H), 3.42-3.35 (m, 1H), 3.06 (s, 1H), 2.89 (s, 1H), 1.81 (d,J=8.3 Hz, 6H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA), m/z:M+1 obs=542.5; t_(R)=2.91 min.

4-(4-(3-(5-Chloro-1H-indol-1-yl)propanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method A. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (100 mg, 0.29mmol), 3-(5-chloro-1H-indol-1-yl)propanoic acid (65 mg, 0.29 mmol), HATUreagent (220 mg, 0.58 mmol), sodium bicarbonate (74 mg, 0.87 mmol), andDMF/CH₂Cl₂—1/1 (0.50 mL) to obtain the desired amide as a white solid(50 mg, 0.10 mmol, 32% yield). ¹H NMR (400 MHz, DMSO-d6) δ 12.77 (s,1H), 7.81 (d, J=8.6 Hz, 2H), 7.58-7.53 (m, 2H), 7.49-7.44 (m, 3H), 7.26(d, J=4.6 Hz, 1H), 7.13 (dd, J=2.1, 8.7 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H),6.42-6.41 (m, 1H), 4.47-4.40 (m, 2H), 4.18 (s, 1H), 4.15 (s, 1H),3.77-3.74 (m, 4H), 2.94-2.90 (m, 2H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA), m/z: M+1 obs=544.2; t_(R)=3.00 min.

4-(4-(3-(5-Chloro-1H-indol-1-yl)propanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method B. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15mmol), 3-(5-chloro-1H-indol-1-yl)propanoic acid (22 mg, 0.10 mmol), HATUreagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), andDMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10mmol, 32% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA),m/z: M+1 obs=574.0; t_(R)=3.23 min.

4-(4-(2-(5-Chloro-2-methyl-1H-indol-1-yl)propanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method B. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15mmol), 2-(5-chloro-2-methyl-1H-indol-1-yl)propanoic acid (24 mg, 0.10mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid(50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA), m/z: M+1 obs=558.0; t_(R)=3.02 min.

(S)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method B. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15mmol), (S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoicacid (27 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodiumbicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desiredamide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=588.0; t_(R)=3.37 min.

4-(4-(2-Methyl-2-(6-(trifluoromethyl)-1H-indol-1-yl)propanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method B. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15mmol), 2-methyl-2-(6-(trifluoromethyl)-1H-indol-1-yl)propanoic acid (27mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a whitesolid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA), m/z: M+1 obs=592.4; t_(R)=3.04 min.

(R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-methylpentanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method B. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15mmol), (R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-methylpentanoicacid (28 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodiumbicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desiredamide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA), m/z: M+1 obs=602.0; t_(R)=3.50 min.

(S)-4-(4-(2-(2,3-Dichlorophenoxy)propanoyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 14, method B. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15mmol), (S)-2-(2,3-dichlorophenoxy)propanoic acid (23 mg, 0.10 mmol),HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol),and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg,0.10 mmol, 32% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA), m/z: M+1 obs=555.3; t_(R)=2.85 min.

4-(2-Oxo-4-(2-(6-(trifluoromethyl)indolin-1-yl)acetyl)piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 14, method B. The reactionwas set up with4-(2-oxopiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (50mg, 0.15 mmol), 2-(6-(trifluoromethyl)indolin-1-yl)acetic acid (25 mg,0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg,0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a whitesolid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA), m/z: M+1 obs=565.0; t_(R)=2.91 min.

Example 5 2,2,2-Trifluoro-1-(4-phenylpiperidin-1-yl)ethanone

Under an N₂ atmosphere at −78° C., 2,2,2-trifluoroacetic anhydride (19.5g, 12.9 mL, 93.0 mmol) was added to a solution of 4-phenylpiperidine(15.0 g, 93.0 mmol) and triethylamine (13 mL, 93.0 mmol) in CH₂Cl₂ (200mL). The reaction was allowed to warm to RT over a period of 30 minutes.The mixture was partitioned between H₂O and CH₂Cl₂, and the organiclayer was concentrated under reduced pressure. Purification via silicagel chromatography using 7/3 hexanes/EtOAc gave2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone as a clear oil (21.0g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.19 (m, 5H), 4.72-4.67 (m, 1H),4.16-4.12 (m, 1H), 3.28-3.21 (m, 1H), 2.89-2.78 (m, 2H), 2.01-1.96 (m,2H), 1.77-1.66 (m, 2H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=258.1; t_(R)=3.27 min.

4-(1-(2,2,2-Trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride

Chlorosulfonic acid (2 mL) was added to2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (1.0 g, 3.9 mmol) ina single portion, and the reaction was stirred for 20 minutes until gasevolution ceased (exothermic reaction). The solution was poured into amixture of ice water (200 mL) and EtOAc (20 mL). The organic layer wasconcentrated and purified via silica gel chromatography using 8/2hexanes/EtOAc to obtain4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chlorideas a clear oil (1.3 g, 94%). ¹H NMR (400 MHz, CDCl₃) δ 8.02-8.00 (m,2H), 7.48-7.45 (m, 2H), 4.78-4.73 (m, 1H), 4.19 (dd, J=14.0, 1.6 Hz,1H), 3.32-3.25 (m, 1H), 3.02-2.86 (m, 2H), 2.03-2.02 (m, 2H), 1.81-1.70(m, 2H).

General Procedure 15, Method A

Under an N₂ atmosphere, a mixture of the sulfonyl chloride (1 mmol), theamine (1 mmol), and pyridine (0.3 mL) was stirred at RT for 19 h. Thecrude product was purified via silica gel chromatography to give thedesired product.

General Procedure 15, Method B

Under an N₂ atmosphere, a mixture of the sulfonyl chloride (1 mmol), theamine (1 mmol), and DABCO (5 equivalents, 5 mmol) in acetonitrile (1.8mL) was heated to 40° C. until the reaction was complete. The crudeproduct was purified via silica gel chromatography to give the desiredproduct.

N-(1,2,4-Thiadiazol-5-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide

Prepared using general procedure 15, method A. Under an N₂ atmosphere, amixture of 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonylchloride (13.0 g, 36.5 mmol), 1,2,4-thiadiazol-5-amine hydrochloride(5.0 g, 36.5 mmol), and pyridine (10 mL) was stirred at RT for 19 h. Thecrude product was purified via silica gel chromatography using 5% MeOHin CH₂Cl₂ givingN-(1,2,4-thiadiazol-5-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamideas a clear oil (2.0 g). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=421.1; t_(R)=2.85 min.

N-(Pyrimidin-4-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide

Prepared using general procedure 15, method B. Prepared using a mixtureof 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonylchloride (2.0 g, 5.6 mmol), 4-aminopyrimidine (535 mg, 5.6 mmol), DABCO(3.1 g, 28.0 mmol) and acetonitrile (10 mL). The reaction mixture washeated at 40° C. for 6 h. Purification via silica gel chromatographyusing 5% MeOH in CH₂Cl₂ gaveN-(pyrimidin-4-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide(850 mg, 36%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=415.3; t_(R)=2.57 min.

N-(Thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide

Prepared using general procedure 15, method A. A solution of441-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride (3g, 8.43 mmol) and 2-aminothiazole (0.84 g, 8.43 mmol) in pyridine (2 ml)was stirred overnight at RT. The reaction was quenched with water,extracted with DCM, dried over Na₂SO₄, filtered and concentrated.Purification via silica gel chromatography using 0-5% methanol in DCMgaveN-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide(1.78 g, 50% yield). LC/MS: (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z M+1 obs=420.3; t_(R)=1.41 min.

General Procedure 16

A solution of sulfonamide (1 equivalent), NaOH (10 equivalents), and H₂O(0.25 M) was stirred at RT for 1 h, then cooled to 0° C. Acetic acid (10equivalents) was added, and the reaction was stirred at 0° C. for 20min. The formed precipitate was filtered off and dried under vacuum togive the desired product.

4-(Piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Prepared using general procedure 16. A mixture ofN-(1,2,4-thiadiazol-5-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide(2.0 g, 4.8 mmol), NaOH (1.92 g, 48.0 mmol), and H₂O (25 mL) was stirredat RT for 30 minutes. An aqueous 1.0 N HCl solution was added (48.0 mL,48 mmol), and the mixture was azeotroped with MeOH (3×100 mL). A 9:1solution of CH₂Cl₂ and MeOH (100 mL) was added, and the mixture wasfiltered to remove NaCl. The filtrate was concentrated under reducedpressure to give4-(piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as aclear oil which solidified upon standing (1.5 g, 96%). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=325.3; t_(R)=0.99 min.

4-(Piperidin-4-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Prepared using general procedure 16. A mixture ofN-(pyrimidin-4-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide(850 mg, 2.1 mmol), NaOH (412 mg, 10.3 mmol), and H₂O (3 mL) was stirredat RT for 30 minutes. A 1.0 N aqueous HCl solution was added (10.3 mL,10.3 mmol), and the mixture was azeotroped with MeOH (3×50 mL). A 1:1solution of CH₂Cl₂ and MeOH (10 mL) was added, and the mixture wasfiltered to remove NaCl. The filtrate was concentrated under reducedpressure to give 4-(piperidin-4-yl)-N-(pyrimidin-4-yl)benzenesulfonamideas a light yellow solid (710 mg). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=319.1; t_(R)=0.43 min.

4-(Piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 16. ToN-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide(1.5 g, 3.57 mmol) was added a solution of NaOH (1.43 g in 25 ml ofH₂O). The reaction was stirred at RT for 30 minutes. The pH was adjustedto 10 with HOAc, and the product crashed out as a pink solid which wasthen filtered, azeotroped with acetonitrile and dried to give4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (1 g, 87% yield).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=324.3;t_(R)=0.46 min.

General Procedure 17, Method A

A mixture of the amine (0.15 mmol), carboxylic acid (0.15 mmol), BOPreagent (100 mg, 0.23 mmol), triethylamine (32 μL, 0.23 mmol), and DMF(0.3 mL) was stirred under an N₂ atmosphere at RT for 19 h. Purificationvia reverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)gave the desired product.

General Procedure 17, Method B

A mixture of the amine (0.15 mmol), carboxylic acid (0.15 mmol), HATU(0.15 mmol), triethylamine (0.15 mmol), and CH₃CN (0.3 mL) was stirredunder an N₂ atmosphere at RT for 19 h. Purification via reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

General Procedure 17, Method C

A mixture of the amine (0.15 mmol), carboxylic acid (0.15 mmol), HATU(0.19 mmol), DIEA (0.3 mmol), and THF (0.3 mL) or DMF (0.3 mL) wasstirred under an N₂ atmosphere at RT for 19 h. Purification via reversephase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave thedesired product.

4-(1-(3-(5-Chloro-1H-indol-1-yl)propanoyl)piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 17, method A. Yield: 23%, ¹HNMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.60 (s,1H), 7.53 (d, J=4.0 Hz, 2H), 7.48 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.14(d, J=8.7 Hz, 1H), 6.43 (s, 1H), 4.54-4.39 (m, 3H), 3.80 (d, J=13.7 Hz,2H), 3.03-2.92 (m, 2H), 2.85-2.75 (m, 2H), 1.67 (d, J=12.5 Hz, 1H), 1.55(d, J=12.4 Hz, 1H), 1.30-1.15 (m, 1H), 1.10-1.02 (m, 1H). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=530.1; t_(R)=3.18 min.

4-(1-(2-(3-Chloro-4-fluorophenoxy)acetyl)piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 17, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=511.2; t_(R)=3.15 min.

4-(1-(2-(6-Chloro-1H-indol-1-yl)acetyl)piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 17, method B. Yield 42%. ¹HNMR (400 MHz, acetic acid-d4) δ 8.46 (s, 1H), 7.77 (d, J=8.3 Hz, 2H),7.55 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 7.32 (s, 1H), 7.03 (d,J=10.2 Hz, 1H), 6.54 (d, 1H), 5.35-5.22 (m, 2H), 4.47 (d, J=13.2 Hz,1H), 4.09 (d, J=12.7 Hz, 1H), 3.22 (t, J=12.2 Hz, 1H), 2.93 (t, J=10.3Hz, 1H), 2.70 (t, J=11.9 Hz, 1H), 1.90-1.68 (m, 3H), 1.64-1.50 (m, 1H).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=516.2;t_(R)=3.06 min.

(R)-4-(4-(2-(4-Fluoro-1H-indol-1-yl)propanoyl)piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 17, method A. Yield: 42%.LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=514.3t_(R)=3.10 min.

2-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid

To a solution of NaOH (5.19 g, 129.8 mmol) in water (10 mL) was addedtetrabutylammonium bromide (0.35 g, 1.08 mmol),5-chloro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 9.83 mmol), toluene (60 mL)and methyl 2-bromoacetate (9 g, 59 mmol). The reaction was heatedovernight at 100° C. The reaction was quenched with water, the layerswere separated and the aqueous layer was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate solutionin THF was treated with NaOH and stirred at RT for 5 hours. The reactionmixture was then diluted with water and the pH was adjusted to 1 with 1NHCl to crash out the product. The reaction was then filtered, azeotropedwith acetonitrile and dried to give2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid. (2 g, 97% yield).¹H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=2.3 Hz, 1H), 8.05 (d, J=2.3 Hz,1H), 7.57 (d, J=3.5 Hz, 1H), 6.42 (d, J=3.5 Hz, 1H), 4.74 (s, 2H). LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=211.1;t_(R)=1.10 min.

4-(1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 17, method C using THF assolvent. To a solution of4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.35 g, 1.08mmol) and 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (0.25 g,1.19 mmol) in THF (6 mL) was added HATU (0.533 g, 1.40 mmol) followed bythe addition of DIEA (0.279 g, 2.16 mmol) at 0° C. under inertatmosphere. The reaction was quenched with water after 15 minutes, thelayers were separated and the aqueous layer was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. Purification via silica gel chromatography using 0-3%methanol in DCM gave4-(1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide(0.26 g, 46% yield). ¹H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.22 (d,J=2.3 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d,J=3.5 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.26 (d, J=4.6 Hz, 1H), 6.83 (d,J=4.6 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H), 5.25 (d, J=2.6 Hz, 2H), 4.44 (d,J=12.9 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.24 (t, J=11.7 Hz, 1H),2.95-2.88 (m, 1H), 2.70 (t, J=11.7 Hz, 1H), 1.91-1.66 (m, 3H), 1.55-1.45(m, 1H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=516.5; t_(R)=1.57 min.

3-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoic acid

To a solution of NaOH (5.19 g, 129.8 mmol) in water (10 mL) was addedtetrabutylammonium bromide (0.35 g, 1.08 mmol),5-chloro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 9.83 mmol), toluene (60 mL)and methyl 3-bromopropanoate (9.8 g, 59 mmol). The reaction mixture washeated overnight at 100° C. The reaction was quenched with water, thelayers were separated and the aqueous layer was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. 3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoatesolution in THF was treated with NaOH and stirred at RT for 5 hours. Thereaction mixture was diluted with water and the pH was adjusted to 1with 1N HCl to crash out the product. The reaction was then filtered,azeotroped with acetonitrile and dried to give3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoic acid. (1.97 g, 90%yield). ¹H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=2.3 Hz, 1H), 8.09 (d,J=2.3 Hz, 1H), 7.64 (d, J=3.5 Hz, 1H), 6.46 (d, J=3.5 Hz, 1H), 4.46 (t,J=7.0 Hz, 2H), 2.82 (t, J=7.0 Hz, 3H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=225.3; t_(R)=1.20 min.

4-(1-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 17, method C using THF assolvent. To a solution of4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.1 g, 0.31 mmol)and 3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoic acid (0.076 g,0.34 mmol) in THF (2 mL) was added HATU (0.153 g, 0.40 mmol) followed bythe addition of DIEA (0.08 g, 0.62 mmol) at 0° C. under inertatmosphere. The reaction was quenched with water after 15 minutes, thelayers were separated and the aqueous layer was extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. Purification via silica gel chromatography using 0-3%methanol in DCM gave4-(1-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide(0.09 g, 55% yield). ¹H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=2.3 Hz, 1H),8.09 (d, J=2.3 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.68 (d, J=3.5 Hz, 1H),7.32 (d, J=8.4 Hz, 2H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H),6.47 (d, J=3.5 Hz, 1H), 5.76 (s, 1H), 4.54-4.48 (m, 3H), 3.87 (d, J=13.7Hz, 1H), 3.04-2.96 (m, 2H), 2.90-2.76 (m, 2H), 1.75-1.64 (m, 2H),1.38-1.16 (m, 2H). LC/MS: m/z 530.06 (M+H)⁺ at 1.55 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

4-(1-(2-(6-Chloro-1H-indol-1-yl)acetyl)piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 17, method C using DMF assolvent. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=515.5; t_(R)=1.68 min.

(R)-4-(1-(2-(4-Fluoro-1H-indol-1-yl)propanoyl)piperidin-4-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 17, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=508.5; t_(R)=2.91 min.

4-(1-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)acetyl)piperidin-4-yl)-N-(pyrimidin-4-yl)benzenesulfonamide

Synthesized according to general procedure 17, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=526.3; t_(R)=2.93 min.

Example 6 General Procedure 18

Bromide (1 equivalent, 1 mmol) was dissolved in dry THF (1 mmol) under anitrogen atmosphere and cooled to <−90° C. n-BuLi (2.5 M in hexanes, 2equivalents, 2 mmol) was added slowly via a syringe at such rate thatthe internal temperature did not exceed −85° C. The resulting darksuspension was left stirring at <−90° C. for half an hour.N—BOC-4-piperidone was added at once to the reaction mixture at −90° C.and the mixture was allowed to slowly warm to room temperature. At roomtemperature the reaction was quenched by addition of saturated aqueousammonium chloride solution and evaporated to dryness. Ethyl acetate andaqueous ammonium chloride were added to the residue. The organic phasewas washed with brine and silica was added to the organic phase beforeit was evaporated to dryness. The product was purified by columnchromatography.

tert-Butyl-4-hydroxy-4-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-piperidine-1-carboxylate

Prepared using general procedure 18. Bromide (5.7 g, 17.9 mmol) wasdissolved in dry THF (3.7 g, 18.6 mmol) under a nitrogen atmosphere andcooled to <−90° C. n-BuLi (2.5 M in hexanes, 14.3 mL, 35.8 mmol) wasadded slowly via a syringe at such rate that the internal temperaturedid not exceed −85° C. The resulting dark suspension was left stirringat <−90° C. for half an hour. N—BOC-4-piperidone was added at once tothe reaction mixture at −90° C. and the mixture was allowed to slowlywarm to room temperature. At room temperature the reaction was quenchedby the addition of 10 mL saturated aqueous ammonium chloride solutionand evaporated to dryness. Ethyl acetate (200 mL) and half saturatedaqueous ammonium chloride (300 mL) were added to the residue. Theorganic phase was washed with brine and 10 g of silica were added to theorganic phase before it was evaporated to dryness. Purification viasilica gel chromatography using 10-100% ethyl acetate in hexane gavetert-butyl-4-hydroxy-4-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidine-1-carboxylate(4.7 g, 59%) as a pink solid. ¹H-NMR (300 MHz, DMSO-d6): δ 12.67 (s,1H), 7.71 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.22 (d, J=4.5 Hz,1H), 6.80 (d, J=4.5 Hz, 1H), 3.56-3.79 (m, 2H), 3.20-3.00 (m, 2H),1.78-1.67 (m, 2H), 1.56-1.36 (m, 2H), 1.39 (s, 9H).

General Procedure 19

To a suspension of the Boc amine (1 equivalent, 1 mmol) indichloromethane (45 mL) was added trifluoroacetic acid (2 mL) and theresulting clear solution was stirred at room temperature for one hour.The solution was evaporated to dryness under reduced pressure at 30° C.The residue was stirred with ethyl acetate and the solid was collectedby filtration. The desired products were obtained by washing thefiltrate with water and organic solvents.

4-(4-Hydroxypiperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 19. To a suspension oftert-Butyl-4-hydroxy-4-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-piperidine-1-carboxylate(4.7 g, 11 mmol) in dichloromethane (500 mL) was added trifluoroaceticacid (23 mL) and the resulting clear solution was stirred at roomtemperature for one hour. The solution was evaporated to dryness underreduced pressure at 30° C. The residue was stirred with ethyl acetate(100 mL) and the solid was collected by filtration and washed with ethylacetate (2×) to yield the trifluoroacetic acid salt. This solid wasstirred with saturated aqueous sodium bicarbonate solution (25 mL) andthe solid was collected by filtration, washed with water (2×), ethanol(2×), TBME (2×), and dried under vacuum at 50° C. to give4-(4-hydroxypiperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (2.9 g,79%) as a pink solid. ¹H-NMR (300 MHz, DMSO-d6): δ 7.69 (d, J=8.4 Hz,2H), 7.37 (d, J=8.4 Hz, 2H), 6.99 (d, J=3.8 Hz, 1H), 6.53 (d, J=3.8 Hz,1H), 3.28-3.13 (m, 4H), 2.11-2.00 (m, 2H), 1.72-1.40 (m, 2H).

General Procedure 20

A solution of carboxylic acid (0.088 mmol, 1 equivalent) and HATU (0.088mmol, 1 equivalent) in DMF (1 mL) was stirred under an N₂ atmosphere at0° C. for 1 h. To this mixture,4-(piperidin-4-ol)-N-(thiazol-2-yl)benzenesulfonamide (0.088 mmol, 1equivalent) and NaHCO₃ (1-2 equivalents) were added under an N₂atmosphere at RT, and the reaction was stirred for 16 h. The reactionmixture was filtered and purified by Gilson preparative HPLC (5-99%CH₃CN—H₂O) to isolate the desired product.

4-((S)-2-(2,3-Dichlorophenoxy)propanoyl)-piperidin-4-ol)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 20. A solution of(S)-2-(2,3-dichlorophenoxy) propanoic acid (20 mg, 0.088 mmol) and HATU(33.5 mg, 0.088 mmol) in DMF (1 mL) was stirred under an N₂ atmosphereat 0° C. for 16 h. To this mixture,4-(piperidin-4-ol)-N-(thiazol-2-yl)benzenesulfonamide (30 mg, 0.088mmol) and NaHCO₃ (7 mg, 0.088 mmol) were added under an N₂ atmosphere atRT, and the reaction was stirred for 16 h. The reaction mixture wasfiltered and purified by Gilson preparative HPLC (5-99% CH₃CN—H₂O) toisolate4-((S)-2-(2,3-dichlorophenoxy)propanoyl)-piperidin-4-ol)-N-(thiazol-2-yl)benzenesulfonamide(3 mg, 10%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=556.2; t_(R)=2.95 min.

4-(1-(2-(6-Chloro-1H-indol-1-yl)acetyl)-4-hydroxypiperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 20. A solution of2-(6-chloro-1H-indol-1-yl)acetic acid (184 mg, 0.88 mmol) and HATU (335mg, 0.88 mmol) in DMF (3 mL) was stirred under an N₂ atmosphere at 0° C.for 1 h. To this mixture,4-(4-hydroxypiperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (300 mg,0.88 mmol) and NaHCO₃ (148 mg, 1.76 mmol) were added under an N₂atmosphere at RT, and the reaction was stirred for 16 h. The reactionmixture was filtered and purified by Gilson preparative HPLC (5-99%CH₃CN—H₂O) to isolate4-(1-(2-(6-chloro-1H-indol-1-yl)acetyl)-4-hydroxypiperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide(246 mg, 52%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=531.3; t_(R)=2.98 min. ¹H NMR (400 MHz, DMSO-d6) 6, 7.78 (d,J=8.5 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 7.29 (dd,J=28.5, 3.9 Hz, 2H), 7.03 (dd, J=9.3, 0.9 Hz, 1H), 6.83 (d, J=4.6 Hz,1H), 6.47 (d, J=3.1 Hz, 1H), 5.23 (q, J=14.8 Hz, 2H), 4.27 (d, J=12.1Hz, 1H), 3.87 (d, J=12.6 Hz, 1H), 3.51 (t, J=11.9 Hz, 1H), 3.02 (t,J=11.6 Hz, 1H), 2.04-1.97 (m, 1H), 1.81 (m, 1H), 1.67-1.61 (m, 2H).

Example 7 General Procedure 21

A solution of the bromide (1 equivalent, 1 mmol), tert-butylazetidin-3-ylcarbamate acetate (1.1 equivalent, 1.1 mmol) sodiumtert-butoxide (4.2 equivalents, 4.2 mmol),biphenyl-2-yl-di-tert-butylphosphine (0.12 equivalents, 0.12 mmol), andPd₂(dba)₃ (0.03 equivalents, 0.03 mmol) in toluene (2.5 mL) was stirredat 75° C. for 16 h. The reaction mixture was poured into H₂O, and the pHwas adjusted to 6. The aqueous layer was extracted with CH₂Cl₂, and theorganics were combined, washed with saturated aqueous NaCl solution,dried over MgSO₄, and concentrated. Purification via silica gelchromatography gave the desired products.

tert-Butyl 1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-ylcarbamate

Prepared according to general procedure 21. A solution of4-bromo-N-(thiazol-2-yl)benzenesulfonamide (2.0 g, 6.3 mmol), tert-butylazetidin-3-ylcarbamate acetate (1.61 g, 6.9 mmol) sodium tert-butoxide(2.55 g, 26.5 mmol), biphenyl-2-yl-di-tert-butylphosphine (224 mg, 0.76mmol), and Pd₂(dba)₃ (172 mg, 0.19 mmol) in toluene (16 mL) was stirredat 75° C. for 16 h. The reaction mixture was poured into H₂O, and the pHwas adjusted to 6. The aqueous layer was extracted 4 times with CH₂Cl₂,and the organics were combined, washed with saturated aqueous NaClsolution, dried over MgSO₄, and concentrated. Purification via silicagel chromatography using 50-70% EtOAc in hexanes gave tert-butyl1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-ylcarbamate (0.86 g,33%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=411.0; t_(R)=2.54 min.

General Procedure 22

TFA (1.4 mL) was added dropwise to a solution of tert-butylazetidinylcarbamate (1 equivalent, 1 mmol) in CH₂Cl₂ (10 mL), and thereaction was stirred at RT for 2 h. After evaporation of the solventsunder reduced pressure, the residue was co-evaporated with EtOH.Trituration with Et₂O:CH₂Cl₂ gave desired products as TFA salts.

4-(3-Aminoazetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared according to general procedure 22. TFA (3.0 mL) was addeddropwise to a solution of tert-butyl1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-ylcarbamate (0.86 g, 2.1mmol) in CH₂Cl₂ (20 mL), and the reaction was stirred at RT for 2 h.After evaporation of the solvents under reduced pressure, the residuewas co-evaporated with EtOH. Trituration using a 9:1 mixture ofEt₂O:CH₂Cl₂ gave a tan solid which was identified as4-(3-aminoazetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide as a TFAsalt (0.83 g, 93%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=311.0; t_(R)=0.48 min.

General Procedure 23

N,N-Diisopropylethylamine (78 μL, 0.45 mmol) was added to a solution ofthe amine (64 mg, 0.15 mmol), the acid (0.22 mmol) and HATU (91 mg, 0.24mmol) in acetonitrile (0.4 mL), and the reaction was stirred at RT for16 h. Purification via reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA) gave the desired product.

2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)propanamide

Synthesized according to general procedure 23. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=532.2; t_(R)=3.11 min.

1-(2,4-Dichlorophenyl)-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)cyclopropanecarboxamide

Synthesized according to general procedure 23. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=523.2; t_(R)=3.04 min.

(S)-2-(1H-indol-1-yl)-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)propanamide

Synthesized according to general procedure 23. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=482.0; t_(R)=2.73 min.

3,4-Dichloro-N-{1-[4-(thiazol-2-ylsulfamoyl)-phenyl]-azetidin-3-yl}-benzamide

Synthesized according to general procedure 23. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=483.2; t_(R)=2.90.

General Procedure 24

A solution of bromide (1 equivalent, 1 mmol), tert-butylazetidin-3-ylmethylcarbamate acetate (1.1 equivalent g, 1.1 mmol) sodiumtert-butoxide (4.2 equivalents, 4.2 mmol),biphenyl-2-yl-di-tert-butylphosphine (0.12 equivalents, 0.12 mmol), andPd₂(dba)₃ (0.03 equivalents, 0.03 mmol) in toluene (2.5 mL) was stirredat 75° C. for 16 h. The reaction mixture was poured into H₂O, and the pHwas adjusted to 6. The aqueous layer was extracted with CH₂Cl₂, and theorganics were combined, washed with saturated aqueous NaCl solution,dried over MgSO₄, and concentrated. Purification via silica gelchromatography gave the desired products.

tert-Butyl-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)methylcarbamate

Prepared using general procedure 24. A solution of4-bromo-N-(thiazol-2-yl)benzenesulfonamide (2.0 g, 6.3 mmol), tert-butylazetidin-3-ylmethylcarbamate acetate (1.71 g, 6.93 mmol), sodiumtert-butoxide (2.55 g, 26.5 mmol), biphenyl-2-yldi-tert-butylphosphine(224 mg, 0.76 mmol), and Pd2(dba)₃ (172 mg, 0.19 mmol) in toluene (16mL) was stirred at 75° C. for 16 h. The reaction mixture was poured intoH2O, and the pH was adjusted to 6. The aqueous layer was extracted 4times with CH2Cl2, and the organics were combined, washed with saturatedaqueous NaCl solution, dried over MgSO4, and concentrated. Purificationvia silica gel chromatography using 50-90% EtOAc in hexanes gavetert-butyl-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)methylcarbamate(0.58 g, 22%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z:M+1 obs=425.0; t_(R)=2.59 min.

General Procedure 25

TFA (1.4 mL) was added dropwise to a solution of tert-butylazetidinylcarbamate (1 equivalent, 1 mmol) in CH2Cl2 (10 mL), and thereaction was stirred at 0° C.—RT for 2 h. After evaporation of thesolvents under reduced pressure, the residue was co-evaporated withEtOH. Trituration with Et₂O:CH₂Cl₂ gave desired products as TFA salts.

4-(3-(Aminomethyl)azetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 25. TFA (2.0 mL) was added to asolution oftert-butyl-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)methylcarbamate(0.58 g, 1.2 mmol) in CH₂Cl₂ (15 mL), and the reaction was stirred from0° C. to RT for 3 h. After evaporating the solvents under reducedpressure, the residue was co-evaporated with EtOH. Trituration using a9:1 mixture of Et₂O:CH₂Cl₂ gave a white solid which was identified as4-(3-(aminomethyl)azetidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(0.65 g) as the TFA salt. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=325.2; t_(R)=0.59 min.

General Procedure 26

N,N-Diisopropylethylamine (78 μL, 0.45 mmol) was added to a solution ofthe amine (83 mg, 0.15 mmol), the acid (0.22 mmol) and HATU (91 mg, 0.24mmol) in acetonitrile (0.4 mL), and the reaction was stirred at RT for16 h. Purification via reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA) gave the desired products.

(S)-2-(4-Fluoro-1H-indol-1-yl)-N-((1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)methyl)propanamide

Synthesized according to general procedure 26. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=514.4; t_(R)=2.74 min.

2-(4-Chloro-3-fluorophenoxy)-N-((1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-yl)methyl)acetamide

Synthesized according to general procedure 26. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=511.2; t_(R)=2.71 min.

Example 8 General Procedure 27

A mixture of 4-bromobenzenesulfonamide (1 equivalent), piperidine (1-10equivalents), Pd₂(dba)₃ (0.02-0.075 equivalents),2-(di-t-butylphosphino)biphenyl (0.08-0.2 equivalents), NaO-tBu (2-6equivalents) and toluene (0.1-0.4 M of 4-bromobenzene sulfonamide) washeated at 70-80° C. for 2-6 h. Purification via silica gelchromatography using 10% MeOH in CH₂Cl₂ (with addition of 1-2%triethylamine) gave the desired product.

tert-Butyl 1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate

Prepared using general procedure 27. A mixture of4-bromo-N-(thiazol-2-yl)benzenesulfonamide (500 mg, 1.57 mmol),tert-butyl piperidin-4-ylcarbamate (314 mg, 1.57 mmol), Pd₂(dba)₃ (43mg, 0.05 mmol), 2-(di-t-butylphosphino)biphenyl (56 mg, 0.19 mmol),NaOtBu (423 mg, 4.4 mmol) and toluene (4 mL) was stirred at 70° C. for 3h. After allowing the mixture to cool to RT, H₂O (50 mL) and EtOAc (50mL) were added. After acidifying with a 1 M HCl solution to pH 4, thelayers were separated, and the aqueous phase was extracted 3 times withCH₂Cl₂ (50 mL). The combined organic extracts were dried over MgSO₄ andabsorbed onto Celite. Purification via silica gel chromatography using10% MeOH in CH₂Cl₂ gavetert-butyl-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-ylcarbamateas an off-white foam (520 mg, 76%). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=439.5; t_(R)=2.56 min.

tert-Butyl-1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate

Prepared using general procedure 27. A mixture of4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (3.7 g, 11.6 mmol),tert-butyl-piperidin-4-ylcarbamate (2.32 g, 11.6 mmol), Pd₂(dba)₃ (319mg, 0.35 mmol), phosphine (415 mg, 1.39 mmol), NaOtBu (3.55 g, 34.8mmol) and toluene (30 mL) was stirred at 70° C. for 3 h. After allowingthe mixture to cool to RT, H₂O (50 mL) and EtOAc (50 mL) were added.After acidifying with a 1 M HCl solution to pH 4, the layers wereseparated, and the aqueous phase was extracted 3 times with CH₂Cl₂ (50mL). The combined organic extracts were dried over MgSO₄ and absorbedonto Celite. Purification via silica gel chromatography using 10% MeOHin CH₂Cl₂ gave tert-Butyl1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)-piperidin-4-ylcarbamateas an off-white foam (357 mg, 70%). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=440.5; t_(R)=2.76 min.

General Procedure 28 Method A

TFA (1.4 mL) was added dropwise to a solution of tert-butyl carbamate (1equivalent, 1 mmol) in CH₂Cl₂ (10 mL), and the reaction was stirred atRT for 2 h. The reaction was worked up or evaporated. Trituration orprecipitation gave desired products.

Method B

Under N₂ atmosphere, a solution of tert-butyl carbamate (1 equivalent,3.74 mmol) in 4 M HCl/dioxane (60 mL) was stirred at RT for 16 hrs. Theformed precipitate was filtered off and washed with dioxane (20 mL), togive the desired products.

4-(4-Aminopiperidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 28, method A. A mixture oftert-butyl-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate(657 mg, 1.5 mmol), TFA (1.5 mL) and CH₂Cl₂ (10 mL) was stirred at RTunder an N₂ atmosphere for 2.5 h. The reaction was poured into saturatedNaHCO₃ solution (50 mL) and acidified to pH 3-4 with a 1 M HCl solution.The mixture was then extracted with CH₂Cl₂ (3×50 mL). Since LCMSanalysis showed that the product was still in the aqueous layer, it wasneutralized with saturated NaHCO₃ resulting in precipitation of a whitesolid which was filtered, washed with MeOH, and dried under vacuum toobtain 4-(4-aminopiperidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (200mg, 38% over 2 steps). ¹H NMR (400 MHz, DMSO-d6) δ 7.57-7.45 (m, 4H),6.94-6.89 (m, 3H), 6.44 (d, J=3.9 Hz, 1H), 3.83 (d, J=13.5 Hz, 2H),3.20-3.14 (m, 1H), 2.83 (t, J=11.8 Hz, 2H), 1.84 (d, J=9.3 Hz, 2H),1.51-1.41 (m, 2H).

4-(4-Aminopiperidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Prepared using general procedure 28, method B. Under N₂ atmosphere, asolution oftert-butyl-1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate(3 g, 7.02 mmol) in 4 M HCl/dioxane (100 mL) was stirred at RT for 16 h.The formed precipitate was filtered off and washed with dioxane (20 mL)to give4-(4-aminopiperidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(1.88 g, 81%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=340; t_(R)=1.28 min.

General Procedure 29

A solution of HATU (38 mg, 0.1 mmol) and triethylamine or DIEA (42 μL,0.3 mmol) in acetonitrile or a 1:1 mixture of CH₂Cl₂ and DMF (1.0 mL)was added to the amine (34 mg, 0.1 mmol) and the acid (0.1 mmol). Thereaction was stirred at RT overnight. After diluting the mixture with a1:1 mixture of DMSO:MeOH (0.5 mL), the reaction was purified via reversephase HPLC (5%-95% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) to give thedesired product.

2-(3-Chloro-4-fluorophenoxy)-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-yl)acetamide

Synthesized according to general procedure 29. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=525.0; t_(R)=2.92 min.

3-(5-Chloro-1H-indol-1-yl)-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-yl)propanamide

Synthesized according to general procedure 29. Yield; 22.5%, LC/MS10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=544.0;t_(R)=3.01 min.

(R)-3-((2-(4-Fluoro-1H-indol-1-yl))-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-yl)propanamide

Synthesized according to general procedure 29. Yield; 35%, LC/MS 10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=529.3; t_(R)=2.90 min.¹H NMR (400 MHz, DMSO-d4) 6, 8.41 (s, 1H), 8.29 (d, J=7.7 Hz, 1H), 7.57(d, J=9.1 Hz, 2H), 7.53 (d, J=3.3 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H),7.13-7.08 (m, 1H), 7.01 (d, J=9.2 Hz, 2H), 6.81 (dd, J=10.6, 7.8 Hz,1H), 6.51 (d, J=3.3 Hz, 1H), 5.12 (q, J=7.0 Hz, 1H), 3.85-3.76 (m, 3H),3.04-2.93 (m, 2H), 1.74 (dd, J=48.6, 12.2 Hz, 1H), 1.64 (d, J=7.0 Hz,4H), 1.50-1.31 (m, 2H).

3-(7-Chloro-1H-indol-1-yl)-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-yl)acetamide

Synthesized according to general procedure 29. Yield; 31%, LC/MS 10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=531.3; t_(R)=2.84 min.¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.58(d, J=9.1 Hz, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.10 (d, J=7.6Hz, 1H), 7.02-6.97 (m, 3H), 6.50 (d, J=3.2 Hz, 1H), 5.09 (s, 2H), 3.82(d, J=13.4 Hz, 3H), 3.00 (t, J=11.2 Hz, 2H), 1.79 (d, J=9.4 Hz, 2H),1.49-1.40 (m, 2H).

2,4-Dichloro-N-(1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-yl)benzamide

Synthesized according to general procedure 29. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=511.0; t_(R)=2.85 min.

General Procedure 30

A mixture of 4-bromobenzenesulfonamide (1 equivalent), piperidine (1equivalents), Pd₂(dba)₃ (0.02-0.075 equivalents),4,5-bis(diphenyl)phosphino-9,9-dimethyl xanthene (0.08-0.3-0.8equivalents) or 2-(di-t-butylphosphino)biphenyl (0.08-0.2 equivalents),NaO-tBu (2-6 equivalents) and 1,4-dioxane or toluene (0.1-0.4 M of4-bromobenzenesulfonamide) was heated at 80° C. for 1-2 h. Purificationvia silica gel chromatography using 10% MeOH in CH₂Cl₂ (with addition of1-2% triethylamine) gave the desired product.

4-(4-(6-Chloro-1,2,3,4-tetrahydroquinoline-1-carbonyl)piperidin-1-yl)N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 30 using xanthene ligand anddioxane. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=518.3; t_(R)=3.15 min.

4-(1,3-Dihydrospiro[indene-2,4′-piperidine]-1′-yl)-N-(thiazol-2-yl)benenesulfonamide

Synthesized according to general procedure 30 using2-(di-t-butylphosphino) biphenyl and toluene. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=426.1; t_(R)=3.03 min.

Example 9 General Procedure 31

A mixture of 4-bromobenzenesulfonamide (1 equivalent),pyrrolidine-3-carboxylic acid (1-10 equivalents), Pd₂(dba)₃ (0.02-0.075equivalents), 2-(dicyclohexylphosphino)-2′,6′-dimethoxybiphenyl(0.08-0.2 equivalents), NaO-tBu (2-6 equivalents) and toluene (0.1-0.4 Mof 4-bromobenzenesulfonamide) was heated at 80° C. for 2-6 h.Purification via silica gel chromatography using 10% MeOH in CH₂Cl₂(with addition of 1-2% triethylamine) gave the desired product.

1-(4-(N-Thiazol-2-ylsulfamoyl)phenyl)pyrrolidine-3-carboxylic acid

Prepared using general procedure 31. A mixture of4-bromo-N-(thiazol-2-yl)benzenesulfonamide (4.70 g, 14.7 mmol),pyrrolidine-3-carboxylic acid (3.66 g, 22.1 mmol, 1.5 eq.), NaO-t-Bu(7.62 g, 79.3 mmol, 5.4 eq.),2-(dicyclohexylphosphino)-2′,6′-dimethoxybiphenyl (0.722 g, 1.76 mmol,12 mol %) and tris(dibenzylideneacetone)-dipalladium (0.40 g, 3 mol %)in toluene (45 mL) was heated at 100° C. for 20 hours. The brownsuspension was cooled to room temperature. Purification via silica gelchromatography using 1-10% MeOH in CH₂Cl₂ gave1-(4-(N-thiazol-2-ylsulfamoyl)-phenyl)pyrrolidine-3-carboxylic acid(2.26 g, 43%). ¹H NMR (300 MHz, DMSO-d6): δ 7.55 (d, J=8 Hz, 2H); 7.17(dd, J=4.7, 1.1 Hz, 1H); 6.73 (dd, J=4.7, 1.1 Hz, 1H); 6.55 (d, J=8 Hz,2H); 3.50-3.23 (m, 4H, partly obscured by water from DMSO-d6); 3.20-3.15(m, 1H); 2.23-2.09 (m, 2H).

General Procedure 32

To the carboxylic acid (1.5 equivalent, 0.17 mmol) and NaHCO₃ (1.5equivalent, 0.17 mmol) was added HATU (1.5 equivalent, 0.17 mmol) in DMF(0.15-0.25 M, 0.25 mL). A solution of amine (1 equivalent, 0.11 mmol) inDMF (0.15-0.25 M, 0.25 mL) was then added and the reaction mixture wasstirred at RT for 19 h. Purification via reverse phase HPLC using10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

4-(3-(1,2,3,4-Tetrahydroquinoline-1-carbonyl)pyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 32. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=469; t_(R)=1.59 min.

4-(3-(6-Fluoro-1,2,3,4-tetrahydroquinoline-1-carbonyl)pyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 32. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=487; t_(R)=1.61 min.

Example 10 General Procedure 33

A mixture of 3-bromobenzene-1-sulfonyl chloride (17.61 mmol, 1equivalent), amino heterocycle (17.61 mmol, 1 equivalent) and pyridine(2.2-4.4 M) was stirred under an N₂ atmosphere at RT for 19 h.Purification via silica gel chromatography using 5% MeOH in CH₂Cl₂ gavethe desired product.

3-Bromo-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 33. Yield: 55%. ¹H NMR (400MHz, DMSO-d6) δ 7.89 (t, J=1.8 Hz, 1H), 7.83-7.79 (m, 1H), 7.52 (t,J=7.9 Hz, 2H), 7.10 (dd, J=168.4, 4.6 Hz, 2H). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=319.0; t_(R)=2.56 min.

General Procedure 34

A mixture of 3-bromobenzenesulfonamide (3.14 mmol, 1 equivalent),tert-butyl piperazine-1-carboxylate (3.76 mmol, 1.2 equivalents),Pd₂(dba)₃ (0.23 mmol, 0.02-0.075 equivalents),2-(di-t-butylphosphino)biphenyl (0.314 mmol, 0.08-0.2 equivalents),NaO-tBu (12.56 mmol, 2-6 equivalents) and toluene (0.1-0.4 M of3-bromobenzenesulfonamide) was heated at 80° C. for 2-6 h. Purificationvia silica gel chromatography using 10% MeOH in CH₂Cl₂ (with addition of1-2% triethylamine) gave the desired product.

tert-Butyl 4-(3-(N-thiazol-2-ylsulfamoyl)phenyl)piperazine-1-carboxylate

Synthesized according to general procedure 34. Yield: 82%. ¹H NMR (400MHz, DMSO-d6) δ 7.39-7.13 (m, 5H), 6.81 (d, J=4.6 Hz, 1H), 3.60-3.13 (m,8H), 1.42 (s, 9H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=425.2; t_(R)=3.24 min.

General Procedure 35

Under N₂ atmosphere, a solution of tert-butyl carbamate (1 equivalent,3.74 mmol) in 4 M HCl/dioxane (60 mL) was stirred at RT for 16 hrs. Theformed precipitate was filtered off and washed with dioxane (20 mL),gave desired products.

4-(piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 35. Under N₂ atmosphere, a solution oftert-butyl 4-(3-(N-thiazol-2-ylsulfamoyl)phenyl)piperidine-1-carboxylate(1 g, 2.35 mmol) in 4 M HCl/dioxane (117 mL) was stirred at RT for 16hrs. The formed precipitate was filtered off and washed with dioxane (20mL) to give 4-(piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.405g, 53%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=324; t_(R)=1.28 min.

General Procedure 36

To the carboxylic acid (1.5 equivalent, 0.17 mmol) and NaHCO₃ (1.5equivalent, 0.17 mmol) was added HATU (1.5 equivalent, 0.17 mmol) in DMF(0.15-0.25 M, 0.25 mL). A solution of the amine (1 equivalent, 0.11mmol) in DMF (0.15-0.25 M, 0.25 mL) was then added and the reactionmixture was stirred at RT for 19 h. Purification via reverse phase HPLCusing 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

(S)-3-(4-(2-(2,3-Dichlorophenoxy)propanoyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 36. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=542; t_(R)=3.22 min.

(S)-3-(4-(2-(4-Fluoro-1H-indol-1-yl)propanoyl)piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 36. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=514; t_(R)=3.08 min.

Example 11 2,2,2-Trifluoro-1-(2-phenylpyrrolidin-1-yl)ethanone

Under an N₂ atmosphere at −78° C., 2,2,2-trifluoroacetic anhydride (5.0g, 33.9 mmol) was added dropwise to a solution of 2-phenylpyrrolidine(4.7 mL, 33.8 mmol), triethylamine (4.7 mL, 33.9 mmol), and CH₂Cl₂ (50mL). The reaction was allowed to warm to RT over a period of 30 minutes.After evaporating the solvents under reduced pressure, purification viasilica gel chromatography using 7/3 hexanes/EtOAc gave2,2,2-trifluoro-1-(2-phenylpyrrolidin-1-yl)ethanone as a white solid(6.1 g, 62%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=244.3; t_(R)=3.17 min.

4-(1-(2,2,2-Trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonyl chloride

At 0° C., 2,2,2-trifluoro-1-(2-phenylpyrrolidin-1-yl)ethanone (2.0 g,8.2 mmol) was added to chlorosulfonic acid (10 mL) and allowed to warmto 25° C. over 30 min. Then the mixture was poured into ice water andextracted with EtOAc. The organic layer was concentrated to obtain4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonyl chlorideas a clear oil which was used in the next reaction step without furtherpurification.

General Procedure 37

Under an N₂ atmosphere, a mixture of the4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonyl chloride(1 equivalent, 1 mmol), the amino heterocycle (1 equivalent, 1 mmol),and pyridine (0.7 mL) was stirred at RT for 19 h. The crude product waspurified via silica gel chromatography and tituration to give thedesired products.

N-(Thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonamide

Prepared using general procedure 37. Under an N₂ atmosphere, a mixtureof the 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonylchloride (1.1 g, 5.8 mmol), 2-aminothiazole (0.58 g, 5.8 mmol), andpyridine (4.0 mL) was stirred at RT for 19 h. The crude product waspurified via silica gel chromatography using 3% MeOH in CH₂Cl₂. Theresulting oil was taken up in a 2:1 mixture of CH₂Cl₂:Et₂O (12 mL) andcooled to 0° C. for 20 minutes. The formed precipitate was filtered offand dried under vacuum to obtainN-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-sulfonamideas a white solid (750 mg, 32%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=405.1; t_(R)=2.68 min.

General Procedure 38

A solution of sulfonamide (1 equivalent), NaOH (10 equivalents), and H₂O(0.25 M) was stirred at RT for 1 h, then cooled to 0° C. Acetic acid (10equivalents) was added, and the reaction was stirred at 0° C. for 20min. The formed precipitate was filtered off and dried under vacuum togive the desired product

4-(Pyrrolidin-2-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 38. A solution ofN-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonamide(750 mg, 1.8 mmol), NaOH (221 mg, 5.5 mmol), and H₂O (2.5 mL) wasstirred at RT for 1 h, then cooled to 0° C. Hydrochloric acid (0.45 mL,5.5 mmol) was added, and the reaction was stirred at 0° C. for 20 min.The formed precipitate was filtered off and dried under vacuum to give4-(pyrrolidin-2-yl)-N-(thiazol-2-yl)benzenesulfonamide (300 mg, 53%).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=310.3;t_(R)=0.44 min.

General Procedure 39

A solution of the sulfonamide (1 equivalent), BOP-reagent (1-1.5equivalent), triethylamine (1-1.5 equivalent), and carboxylic acid(1-1.5 equivalent) in DMF (0.3-0.5 M) was stirred under an N₂ atmosphereat RT for 19 h. Purification via reverse phase HPLC using 10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

4-(1-(2-(6-Chloro-1H-indol-1-yl)acetyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 39. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=501.3; t_(R)=3.08 min.

4-(1-(3-(5-Chloro-1H-indol-1-yl)propanoyl)pyrrolidin-2-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 39. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=515.5; t_(R)=3.18 min.

Example 12 General Procedure 40

To a stirring solution of 2-aminoindan hydrochloride (1.0 mmol),N,N-diisopropylethylamine (2.0 mmol), and acetonitrile (3.4 mL) wasadded the isocyanate (1.0 mmol) dropwise over 10 minutes. The mixturewas stirred at 25° C. for 19 hours. The solution was evaporated todryness and the residue was purified via silica gel chromatography usingEtOAc in hexanes to obtain the desired urea

1-(2-Chloroethyl)-3-(2,3-dihydro-1H-inden-2-yl)urea

Synthesized according to general procedure 40. The reaction was set upwith 2-aminoindan hydrochloride (5.0 g, 29.5 mmol),N,N-diisopropylethylamine (10.3 mL, 58.9 mmol), acetonitrile (100 mL),and 2-chloroethylisocyanate (2.52 mL, 29.5 mmol). Purification viasilica gel chromatography using 50% EtOAc in hexanes gave the desiredurea as a white solid (3.3 g, 13.8 mmol, 47% yield). ¹H NMR (400 MHz,DMSO-d6) δ 7.23-7.18 (m, 2H), 7.15-7.11 (m, 2H), 6.38 (d, J=7.3 Hz, 1H),6.03 (t, J=5.7 Hz, 1H), 4.36-4.28 (m, 1H), 3.57 (t, J=6.2 Hz, 2H),3.38-3.29 (m, 2H), 3.12 (dd, J=7.1, 15.8 Hz, 2H), 2.68 (dd, J=5.5, 15.8Hz, 2H).

1-(4-Chloropropyl)-3-(2,3-dihydro-1H-inden-2-yl)urea

Synthesized according to general procedure 40. The reaction was set upwith 2-aminoindan hydrochloride (2.0 g, 11.8 mmol),N,N-diisoproplyethylamine (4.1 mL, 23.6 mmol), acetonitrile (20 mL), and3-chloropropylisocyanate (1.2 mL, 11.8 mmol). Purification via silicagel chromatography using 80% EtOAc in hexanes gave the desired urea as awhite solid (1.9 g, 7.5 mmol, 64% yield). ¹H NMR (400 MHz, DMSO-d6) δ7.23-7.19 (m, 2H), 7.15-7.11 (m, 2H), 6.13 (d, J=7.3 Hz, 1H), 5.86 (t,J=5.7 Hz, 1H), 4.35-4.27 (m, 1H), 3.62 (t, J=6.5 Hz, 2H), 3.14-3.08 (m,4H), 2.68 (dd, J=5.6, 15.8 Hz, 2H), 1.84-1.78 (m, 2H).

General Procedure 41

-   -   wherein x is 1-2;

To a stirring solution of urea (1.0 mmol) and DMF (3.8 mL) under N₂, at0° C., was added sodium hydride (60% in mineral oil, 1.0 mmol)portionwise over 10 minutes. The mixture was stirred at ambienttemperature for 3 hours. MeOH (1.0 mL) was added and the solution wasevaporated to dryness under reduced pressure. The residue was purifiedvia silica gel chromatography using EtOAc in hexanes to obtain thedesired cyclic urea.

1-(2,3-Dihydro-1H-inden-2-yl)imidazolidin-2-one

Synthesized according to general procedure 41. The reaction was set upwith 1-(2-chloroethyl)-3-(2,3-dihydro-1H-inden-2-yl)urea (4.0 g, 16.8mmol), DMF (15.0 mL), and sodium hydride (60% in mineral oil, 672 mg,16.8 mmol). Purification via silica gel chromatography using 50% EtOAcin hexanes gave the desired cyclic urea as a white solid (1.1 g, 5.4mmol, 30% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.24-7.20 (m, 2H),7.16-7.12 (m, 2H), 6.34 (s, 1H), 4.60-4.53 (m, 1H), 3.23-3.10 (m, 4H),3.08-2.95 (m, H), 2.92-2.86 (m, 2H).

1-(2,3-Dihydro-1H-inden-2-yl)tetrahydropyrimidin-2(1H)-one

Synthesized according to general procedure 41. The reaction was set upwith 1-(4-chlorobutyl)-3-(2,3-dihydro-1H-inden-2-yl)urea (1.0 g, 4.0mmol), DMF, and sodium hydride (60% in mineral oil, 170 mg, 4.0 mmol).Purification via silica gel chromatography using 50% EtOAc in hexanesgave the desired cyclic urea as a white solid (250 mg, 1.2 mmol, 30%yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.22-7.18 (m, 2H), 7.14-7.10 (m,2H), 6.26 (s, 1H), 5.22-5.11 (m, 1H), 3.09-2.87 (m, 8H), 1.76-1.60 (m,2H).

General Procedure 42

To a stirring solution of the aminoheterocycle (2.4 equivalents, 2.4mmol) and pyridine (0.35 mL) under N₂, at 0° C., was added pipsylchloride (1 equivalent, 1 mmol). The mixture was stirred at ambienttemperature for 17 hours. CH₂Cl₂/MeOH-2/1 was added. The mixture wasfiltered and the filtrate was purified via silica gel chromatographyusing MeOH in CH₂Cl₂. The solid was triturated to give the desiredproducts.

4-Iodo-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 42. To a stirring solution of2-aminothiazole (13.2 g, 132.2 mmol) and pyridine (20 mL) under N₂, at0° C., was added pipsyl chloride (20.0 g, 55.1 mmol). The mixture wasstirred at ambient temperature for 17 hours. CH₂Cl₂/MeOH-2/1 (100 mL)was added. The mixture was filtered and the filtrate was purified viasilica gel chromatography using 5% MeOH in CH₂Cl₂. The solid wastriturated with CH₂Cl₂ to obtain the desired sulfonamide as a whitesolid (8.4 g, 20.9 mmol, 38% yield). ¹H NMR (400 MHz, DMSO-d6) δ 12.83(s, 1H), 7.94-7.90 (m, 2H), 7.57-7.54 (m, 2H), 7.26 (d, J=4.6 Hz, 1H),6.86 (d, J=4.6 Hz, 1H).

General Procedure 43

wherein x is 1-2;

Under an N₂ atmosphere, a mixture of the phenyl iodide (1 mmol), cyclicurea (1 mmol), copper(I) iodide (2 mmol), potassium carbonate (3 mmol),and NMP (3.0 mL) was stirred and heated at 220° C. in a sealed tube, viamicrowave, for 20 minutes. The crude product was purified via silica gelchromatography using MeOH in CH₂Cl₂.

4-(3-(2,3-Dihydro-1H-inden-2-yl)-2-oxoimidazolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 43. The reaction was set upwith 4-iodo-N-(thiazol-2-yl)benzenesulfonamide (250 mg, 0.68 mmol),1-(2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one (138 mg, 0.68 mmol),copper(I) iodide (267 mg, 1.4 mmol), potassium carbonate (282 mg, 2.0mmol), and NMP (1.7 mL). The dark mixture was purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ followed by trituration with 50%Et₂O in CH₂Cl₂ to obtain the desired urea as a white solid (32 mg, 0.07mmol, 10% yield). ¹H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.75-7.69(m, 4H), 7.26-7.24 (m, 3H), 7.19-7.17 (m, 2H), 6.81 (d, J=4.5 Hz, 1H),4.74 (dd, J=1.3, 14.2 Hz, 1H), 3.81-3.77 (m, 2H), 3.34-3.27 (m, 2H),3.12 (dd, J=7.9, 16.1 Hz, 2H), 3.00 (dd, J=6.2, 16.1 Hz, 2H). LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=441.2;t_(R)=1.45 min.

4-(3-(2,3-dihydro-1H-inden-2-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 43. The reaction was set upwith 4-iodo-N-(thiazol-2-yl)benzenesulfonamide (250 mg, 0.68 mmol),1-(2,3-dihydro-1H-inden-2-yl)tetrahydropyrimidin-2(1H)-one (138 mg, 0.68mmol), copper(I) iodide (267 mg, 1.4 mmol), potassium carbonate (282 mg,2.0 mmol), and NMP (1.7 mL). The dark mixture was purified via silicagel chromatography using 10% MeOH in CH₂Cl₂ to obtain the desired ureaas a white solid (45 mg, 0.10 mmol, 15% yield). ¹H NMR (400 MHz,DMSO-d6) δ 12.71 (s, 1H), 7.71 (dd, J=1.9, 6.9 Hz, 2H), 7.45 (dd, J=1.9,6.9 Hz, 2H), 7.26-7.21 (m, 3H), 7.23-7.11 (m, 2H), 6.83 (d, J=4.5 Hz,1H), 5.25-5.19 (m, 1H), 3.68-3.65 (m, 2H), 3.20 (t, J=5.9 Hz, 2H),3.09-2.98 (m, 4H), 2.01-1.91 (m, 2H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=455.3; t_(R)=2.98 min.

Example 13 General Procedure 44

A mixture of sulfonamide (1 equivalent, 1 mmol) and maleic anhydride (1equivalent, 1 mmol) was heated under refluxed for 16 hrs. The reactionwas cooled to RT and then 0° C. externally using ice bath for 4 hrs. Theformed precipitate was filtered off and washed with cold water. Thecrude solid was purified via silica gel chromatography using MeOH inCH₂Cl₂ to give the desired products.

(1H-Pyrrole-2,5-dione)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 44. A mixture of sulfathiazole (5 gm,19.5 mmol) and maleic anhydride (1.92 g, 19.5 mmol) was heated underrefluxed for 16 hrs. The reaction was cooled to RT and then to 0° C. for4 hrs. The formed precipitate was filtered off and washed with coldwater. The crude solid was dissolved in CH₂Cl₂ and absorbed onto Celite.Purification via silica gel chromatography using 10% MeOH in CH₂Cl₂ gave(1H-pyrrole-2,5-dione)-N-(thiazol-2-yl)benzene sulfonamide (2 g, 30%).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=336.2;t_(R)=2.12 min.

General Procedure 45

Prepared using general procedure 45. To a solution of(1H-pyrrole-2,5-dione)-sulfonamide (1 equivalent, 1 mmol) in acetic acid(17 mL) was added the amine (3 equivalents, 3 mmol). The reaction wasmicrowaved at 110° C. for 4 hrs. The product was purified bychromatography.

4-(3-(6-Chloro-1,2,3,4-tetrahydroquinoline)-succinimide)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 45. To a solution of(1H-pyrrole-2,5-dione)-N-(thiazol-2-yl)benzenesulfonamide (20 mg, 0.059mmol) in acetic acid (1 mL) was added6-chloro-1,2,3,4-tetrahydroquinoline (30 mg, 0.177 mmol). The reactionwas microwaved at 110° C. for 4 hrs. The reaction mixture was filteredand purified by reverse phase preparative HPLC (5-99% CH₃CN—H₂O) toisolate4-(3-(6-chloro-1,2,3,4-tetrahydroquinoline)-succinimide)-N-(thiazol-2-yl)benzenesulfonamide(3 mg, 10%). LC/MS (10-99% CH₃CN—H₂O). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=503.2; t_(R)=3.29 min.

Example 14 Route 1(R)-5-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-one

To a stirring solution of (R)-(−)-dimethyl-5-oxo-1,2-dioxolane-4-aceticacid (15.8 g, 91 mmol), and THF (90 mL), at 0° C., under N₂, was addedborane-THF complex (1.0 M in THF, 100 mL, 100 mmol) dropwise over 60minutes. The mixture was stirred at 0° C. for 2.5 hours and then allowedto warm to 25° C. The mixture was stirred at room temperature for 19hours. The mixture was poured into MeOH (150 mL) and the solution wasevaporated to dryness under reduced pressure at 25° C. The residue waspurified via silica gel chromatography using 30% EtOAc in hexanes toobtain the desired alcohol as a clear oil (7.1 g, 44.6 mmol, 49% yield).¹H NMR (400 MHz, CDCl₃) δ 4.61-4.51 (m, 1H), 3.89-3.80 (m, 2H),2.20-2.12 (m, 2H), 2.05-1.98 (m, 1H), 1.64 (s, 3H), 1.57 (s, 3H).

(R)-3-Hydroxydihydrofuran-2(3H)-one

A solution of (R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-one(33.0 g, 206 mmol), p-toluenesulfonic acid monohydrate (400 mg, 2.1mmol), and benzene (300 mL) was stirred at 25° C. for 3 hours. Thesolution was evaporated to dryness under reduced pressure at 25° C. Theresidue was purified via silica gel chromatography using 50% EtOAc inhexanes to give the desired lactone as a clear oil (18.0 g, 176 mmol,85% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.57-4.52 (m, 1H), 4.44 (td,J=9.0, 3.6 Hz, 1H), 4.28-4.21 (m, 1H), 3.72 (s, 1H), 2.66-2.58 (m, 1H),2.35-2.24 (m, 1H).

(R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one

To a stirring solution of (R)-3-hydroxydihydrofuran-2(3H)-one (41.0 g,401 mmol), imidazole (61.4 g, 920 mmol), and CH₂Cl₂ (175 mL) at 0° C.,under N₂, was added t-butyldiphenylsilyl chloride (129 mL, 138 g, 497mmol) dropwise over 30 minutes. The mixture was stirred at roomtemperature for 19 hours. The mixture was partitioned between CH₂Cl₂(700 mL) and H₂O (100 mL). The organic portion concentrated to drynessunder reduced pressure. The residue was purified via silica gelchromatography using 50% EtOAc in hexane to give the desired lactone asa white solid (127 g, 373 mmol, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ7.84-7.82 (m, 2H), 7.73-7.71 (m, 2H), 7.50-7.40 (m, 6H), 4.41-4.31 (m,2H), 4.06-4.00 (m, 1H), 2.29-2.19 (m, 2H), 1.10 (s, 9H).

General Procedure 46

To a stirring suspension of the aniline (1.3 mmol) and CH₂Cl₂ (5.5 mL)under N₂, at 0° C., was added trimethylaluminum (1.3 mmol) dropwise over20 minutes. The solution was stirred at ambient temperature for 30minutes. The solution was cooled to 0° C. followed by the dropwiseaddition of (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (1mmol) in CH₂Cl₂ (1.0 mL) over 30 minutes. The solution was stirred atambient temperature for 19 hours. The solution was cooled to 0° C. andaqueous 1.0 M HCl was added dropwise over 1.5 hours. The organic portionwas washed with 1.0 N aqueous HCl (2×1.0 mL) and evaporated to drynessunder reduced pressure. The residue was purified via silica gel usingMeOH in CH₂Cl₂ to obtain the desired amide as a white solid.

(R)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide

Synthesized according to general procedure 46. The reaction was set upwith sulfathiazole (122 g, 477 mmol), CH₂Cl₂ (1.5 L), trimethylaluminum(2.0 M in hexanes, 239 mL, 477 mmol), and(R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (125 g, 367mmol) in CH₂Cl₂ (250 mL). The reaction was purified via silica gel using10% MeOH in CH₂Cl₂ to obtain the desired amide as a white solid (207 g,348 mmol, 95% yield). ¹H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76(dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m,8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1,6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91(m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=596.5; t_(R)=1.93 min.

General Procedure 47

Method A

To a stirring solution of di-tert-butyl-azodicarboxylate (3.0equivalent, 3.0 mmol) and THF (2.0 mL), under N₂, at 0° C., was addedtributylphosphine (3.0 equivalent, 3.0 mmol), dropwise over 5 minutes.The colourless solution was stirred at 0° C. for 30 minutes. A solutionof amidealcohol (1.0 equivalent, 1.0 mmol) in THF (0.60 mL) was addeddropwise over 5 minutes. The solution was stirred at ambient temperaturefor 2 hours. To this solution was added H₂O (40 uL) and the solution wasevaporated to dryness. The residue was purified via silica gel usingEtOAc in hexanes to give the desired lactam.

Method B

The alcohol (1.0 equivalent, 1.0 mmol) in anhydrous DCM (4.0 mL) wasstirred and cooled down to 0° C. To this, a solution of PPh₃ (1.5equivalents, 1.5 mmol) in anhydrous DCM (0.90 mL) was slowly addedfollowed by the slow addition of CBr₄ (1.5 equivalents, 1.5 mmol) inanhydrous DCM (0.90 mL). On completion of CBr₄ addition, the reactionwas maintained at 0° C. for 5 min. The ice bath was removed and thereaction was stirred at room temperature for 4 h. The reaction wasmonitored by LCMS. The reaction was diluted with DCM and the organiclayer was washed with saturated aqueous NaHCO₃ (×2) and brine (×1). Theorganic layer was dried over Na₂SO₄ and concentrated. The crude productwas purified by column chromatography (gradient 0-100% EtOAc/Hexane) toprovide the bromide as a pale yellow solid (9.0 g). To a solution of thebromide (1.0 equivalent, 1.0 mmol) in chloroform (3.5 mL; HPLC grade),DBU (equivalents, 2.0 mmol) was added and stirred at room temperatureunder N₂ atmosphere for ˜1 h. The reaction was monitored by LCMS. Thereaction was diluted with DCM and the organic layer was washed withaqueous 1 N HCl (×3), saturated aqueous NaHCO₃ (×2) and brine (×1). Theorganic layer was dried over Na₂SO₄ and concentrated to provide thedesired lactam as a yellow solid.

(R)-4-(3-(tert-Butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 47, method A. The reactionwas set up with di-tert-butyl-azodicarboxylate (1.81 g, 7.88 mmol), THF(15 mL), tributylphosphine (1.59 g, 7.88 mmol), and(R)-2-(tert-butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide(1.56 g, 2.63 mmol). The residue was purified via silica gel using 40%EtOAc in hexanes to give the desired lactam as a white solid (1.3 g, 2.3mmol, 86% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.83-7.76 (m, 4H), 7.70(dd, J=1.9, 7.0 Hz, 2H), 7.65 (dd, J=1.5, 8.0 Hz, 2H), 7.39-7.29 (m,6H), 7.06 (d, J=4.6 Hz, 1H), 6.44 (d, J=4.6 Hz, 1H), 4.35 (dd, J=7.9,9.2 Hz, 1H), 3.67-3.62 (m, 1H), 3.48-3.42 (m, 1H), 2.18-1.98 (m, 2H)1.11 (s, 9H).

Synthesized according to general procedure 47, method B. The reactionwas set up with(R)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide(10.0 g, 16.78 mmol, 1.0 equiv.), DCM (70 mL), PPh₃ (6.6 g, 25.2 mmol,1.5 equiv.), CBr₄ (8.35 g, 25.2 mmol, 1.5 equiv.), DBU (3.53 mL, 23.58mmol, 2.0 equiv.) The organic layer was dried over Na₂SO₄ andconcentrated to provide the lactam as a yellow solid (6.25 g, 92%). ¹HNMR (400 MHz, DMSO-d6) δ 7.83-7.76 (m, 4H), 7.70 (dd, J=1.9, 7.0 Hz,2H), 7.65 (dd, J=1.5, 8.0 Hz, 2H), 7.39-7.29 (m, 6H), 7.06 (d, J=4.6 Hz,1H), 6.44 (d, J=4.6 Hz, 1H), 4.35 (dd, J=7.9, 9.2 Hz, 1H), 3.67-3.62 (m,1H), 3.48-3.42 (m, 1H), 2.18-1.98 (m, 2H) 1.11 (s, 9H).

General Procedure 48

To a stirring suspension of benzenesulfonamide (1.0 mmol) in CH₂Cl₂ (2.3mL), under N₂, at 0° C., was added N,N-diisopropylethylamine (2.0 mmol)followed by allylbromide (2.0 mmol). The mixture was stirred at ambienttemperature for 19 hours. The mixture was evaporated to dryness underreduced pressure. The residue was purified via silica gel using EtOAc inhexanes to give the desired alkylsulfonamide.

(R)—N-Allyl-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared according to general procedure 48. The reaction was set up(R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(50.0 g, 86.6 mmol), CH₂Cl₂ (200 mL), N,N-diisopropylethylamine (30.2mL, 173.2 mmol), and allylbromide (15.0 mL, 173.2 mmol). The residue waspurified via silica gel using 50% EtOAc in hexanes to give the desiredsulfonamide as a white solid (45.0 g, 72.7 mmol, 84% yield). ¹H NMR (400MHz, DMSO-d6) δ. 7.85-7.79 (m, 6H), 7.70 (dd, J=1.6, 7.7 Hz, 2H),7.49-7.40 (m, 6H), 7.36 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H),5.90-5.82 (m, 1H), 5.16 (dd, J=1.3, 10.3 Hz, 1H), 4.97 (d, J=1.3 Hz,1H), 4.56-4.52 (m, 3H), 3.76-3.72 (m, 1H), 3.56-3.48 (m, 1H), 2.28-2.25(m, 1H), 2.19-1.98 (m, 1H), 1.11 (s, 9H).

(R)—N-Allyl-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

To a stirring solution of(R)—N-allyl-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(78.7 g, 127 mmol) and THF (300 mL) under N₂, at 0° C., was addedtetrabutylammonium fluoride (1.0 M in THF, 255 mL, 255 mmol) dropwiseover 20 minutes. The mixture was stirred at ambient temperature for 2hours. To this solution was added H₂O (5 mL) followed by evaporation todryness. The residue was purified via silica gel using 30% EtOAc inhexanes to obtain the desired alcohol as a white solid (39.5 g, 104mmol, 82% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37(d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd,J=1.3, 10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz,2H), 4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H),2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).

General Procedure 49

Method A

To a stirring solution of alcohol (1.0 mmol) and CH₂Cl₂ (3.0 mL) underN₂, at −40° C., was added N,N-diisopropylethylamine (2.0 mmol) followedby the dropwise addition of triflic anhydride (1.1 mmol) over 20minutes. The mixture was stirred at −40° C. for 1 hour. To this solutionwas added amine (1.5 mmol) at −40° C. The solution was held at aspecific temperature (−20° C. to 25° C.) for a specified time followedby quenching with H₂O (5.5 mmol). The reaction was evaporated to drynessunder reduced pressure. The residue was purified via silica gel usingMeOH in CH₂Cl₂ to obtain the desired lactam.

Method B

Under an N₂ atmosphere at −30° C., N,N-diisopropylethylamine (2-4equivalent) was added dropwise to a solution of alcohol (1 equivalent)in CH₃CN (0.5 M). Trifluoromethanesulfonic anhydride (1.1-2.1equivalent) was added drop wise to this solution maintaining theinternal temperature of the reaction mixture below −30° C. To 0° C.solution of amine/phenol (1.5-3 equivalent) in CH₃CN (0.5 mL) was addeddrop wise, NaH (0.9 equivalent to amine/phenol) in CH₃CN. Uponcompletion of addition, the mixture was stirred at 0° C. for 1 h. Thisamine reaction mixture was added to the above triflate mixture at −30°C. The reaction was allowed to warm up to 0° C. and was kept at thistemperature for 24 h. The reaction mixture was washed with saturatedaqueous sodium bicarbonate (2×), brine, dried over magnesium sulfate,and concentrated. Purification via silica gel chromatography using 0-40%ethyl acetate in hexane gave the desired product.

General Procedure 50

To a stirring suspension of allyl sulfonamide (1.0 mmol) and CH₃CN (3.8mL) was added Pd(PPh₃)₄ (0.2 mmol) and 1,3-dimethylbarbituric acid (10mmol). The mixture was heated at 60° C. for 4 hours. The reaction wasevaporated to dryness under reduced pressure. The residue was purifiedvia silica gel using MeOH in CH₂Cl₂ to obtain the desired sulfonamide.

(S)—N-Allyl-4-(3-(4-chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-21)benzenesulfonamide

Synthesized according to general procedure 49, method A. The reactionwas set up with(R)—N-allyl-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzene-sulfonamide(5.0 g, 13.2 mmol), triflic anhydride (2.43 mL, 14.5 mmol),diisopropylamine (4.6 mL, 26.4 mmol), CH₂Cl₂, and 4-Cl-5-F-indoline (3.4g, 19.8 mmol). The reaction was held at −40° C. for 19 hours andquenched with H₂O (0.10 mL). The residue was purified via silica gelusing 10% MeOH in CH₂Cl₂ followed by trituration with Et₂O/CH₂Cl₂-9/1(20 mL) to obtain the desired alcohol as a white solid (6.8 g, 12.8mmol, 97% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37(d, J=4.7 Hz, 1H), 7.03-6.99 (m, 1H), 6.93 (d, J=4.7 Hz, 1H), 6.48 (dd,J=3.6, 8.7 Hz, 1H), 5.92-5.82 (m, 1H), 5.16 (dd, J=1.3, 10.3 Hz, 1H),4.97 (d, J=1.3 Hz, 1H), 4.80 (dd, J=8.7, 10.9 Hz, 1H), 4.55 (dd, J=1.4,4.0 Hz, 2H), 3.90-3.78 (m, 2H), 3.64-3.58 (m, 1H), 3.41-3.31 (m, 1H),3.07-2.95 (m, 2H), 2.40-2.33 (m, 1H), 2.16-2.13 (m, 1H).

(S)-4-(3-(4-Chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 50. The reaction was set upwith(S)—N-allyl-4-(3-(4-chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (17.5 g, 32.8 mmol), CH₃CN (125 mL), Pd(PPh₃)₄ (7.6 g, 6.6mmol) and 1,3-dimethylbarbituric acid (30.7 g, 196.8 mmol). The formedprecipitate was filtered, washed with CH₃CN/CH₂Cl₂-1/1 (300 mL), andrecrystallized from MeOH/CH₂Cl₂—1/9 to obtain the desired lactam as awhite solid (11.0 g, 22.3 mmol, 68% yield). ¹H NMR (400 MHz, DMSO-d6) δ7.87-7.80 (m, 4H), 7.26 (d, J=4.6 Hz, 1H), 7.03-6.99 (m, 1H), 6.83 (d,J=4.6 Hz, 1H), 6.48 (dd, J=3.6, 8.7 Hz, 1H), 4.80 (dd, J=8.8, 10.8 Hz,1H), 3.90-3.78 (m, 2H), 3.64-3.55 (m, 1H), 3.41-3.32 (m, 1H), 3.08-2.93(m, 2H), 2.40-2.33 (m, 1H), 2.16-2.10 (m, 1H). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=493.2; t_(R)=1.61 min.

(S)—N-Allyl-4-(3-(5,6-dichloro-1H-benzoimidazol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 49, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=548; t_(R)=1.33 min.

(S)-4-(3-(5,6-Dichloro-1H-benzoimidazol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 50. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=548; t_(R)=1.33 min.

(S)—N-Allyl-4-(3-(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 49, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=528; t_(R)=1.71 min.

(S)-4-(3-(7-Chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 50. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=489.3; t_(R)=1.08 min

(S)-Benzyl5-fluoro-1-(2-oxo-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)pyrrolidin-3-yl)spiro[indoline-3,4-piperidine]-1′-carboxylate

Synthesized according to general procedure 49, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=702.5; t_(R)=2.7 min.

(S)-Benzyl5-fluoro-1-(2-oxo-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)pyrrolidin-3-yl)spiro[indoline-3,4-piperidine]-1′-carboxylate

Synthesized according to general procedure 50. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=662.2; t_(R)=1.88 min.

Route 2 General Procedure 51

To a solution of protected TBDPS sulfonamide (1 equivalent) in THF(0.5-1 M) under N₂, was added a solution of tetra butyl ammoniumfluoride in THF (1M, 4 equivalent). Upon completion of addition, themixture was stirred at RT overnight. The reaction mixture was pouredinto water and extracted with CH₂Cl₂ (2×), dried over magnesium sulfate,and concentrated. Purification via silica gel chromatography using 2-10%MeOH in CH₂Cl₂ gave desired product.

(R)-4-(3-Hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide

To a solution of(R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide(5.5 gm, 9.53 mmol) in THF (40 mL) under N₂, was added a solution oftetrabutyl ammonium fluoride in THF (1M, 40 mL, 38.12 mmol). Uponcompletion of addition, the mixture was stirred at RT overnight. Thereaction mixture was poured into water and extracted with CH₂Cl₂ (2×50mL), dried over magnesium sulfate, and concentrated. Purification viasilica gel chromatography using 2-10% MeOH in CH₂Cl₂ gave(R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (2.6 gm, 76%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=340.0; t_(R)=0.54 min.

General Procedure 52 Method A

Under an N₂ atmosphere at −40° C., N,N-diisopropylethylamine (2-4equivalent) was added drop wise to a solution of alcohol (1 equivalent)in CH₂Cl₂ (0.5 M). Trifluoromethanesulfonic anhydride (1.1-2.1equivalent) was added dropwise to this solution maintaining the internaltemperature of the reaction mixture below −40° C. Upon completion ofaddition, the mixture was stirred at −40° C. for 1 h. A solution ofamine/phenol (1.5-3 equivalent) in CH₂Cl₂ (40 mL) was added drop wise tothis solution maintaining the internal temperature of the reactionmixture below −40° C. The reaction was allowed to warm up to −20° C. andwas kept at this temperature for 48 h. The reaction mixture was washedwith saturated aqueous sodium bicarbonate (2×), brine, dried overmagnesium sulfate, and concentrated. Purification via silica gelchromatography using 0-40% ethyl acetate in hexane gave desired product.

Method B

Under an N₂ atmosphere at −30° C., N,N-diisopropylethylamine (2-4equivalent) was added drop wise to a solution of alcohol (1 equivalent)in CH₃CN (0.5 M). Trifluoromethanesulfonic anhydride (1.1-2.1equivalent) was added dropwise to this solution maintaining the internaltemperature of the reaction mixture below −30° C. To 0° C. solution ofamine/phenol (1.5-3 equivalent) in CH₃CN (0.5 mL) was added drop wise,NaH (0.9 equivalent to amine/phenol) in CH₃CN. Upon completion ofaddition, the mixture was stirred at 0° C. for 1 h. This amine reactionmixture was added to above triflate mixture at −30° C. The reaction wasallowed to warm up to 0° C. and was kept at this temperature for 24 h.The reaction mixture was washed with saturated aqueous sodiumbicarbonate (2×), brine, dried over magnesium sulfate, and concentrated.Purification via silica gel chromatography using 0-40% ethyl acetate inhexane gave desired product.

(S)-4-(3-(4-(3,5-Dichlorophenyl)piperazin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 52, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=484; t_(R)=1.66 min.

(S)-4-(3-(Indolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 52, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=441.2; t_(R)=2.93 min.

General Procedure 53

Under an N₂ atmosphere at 0° C., DMAP (1.5-3 equivalent) was added to asolution of alcohol (1 equivalent) in CH₂Cl₂ (0.5 M). To the reactionmixture was then added triethylamine (20 equivalent). Methanesulfonicanhydride (10 equivalent) was added dropwise to this solution at 0° C.Upon completion of addition, the mixture was stirred at RT overnight.The reaction mixture was poured into water and extracted with CH₂Cl₂(2×), dried over magnesium sulfate, and concentrated. Purification viasilica gel chromatography using 2-10% MeOH in CH₂Cl₂ gave mesylatedalcohol. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=498.3; t_(R)=1.18 min.

General Procedure 54

Method A

A solution of mesylate (1 equivalent), Cs₂CO₃ (10 equivalents), phenol(2-5 equivalents) in DMF (0.3-0.5 M) was stirred under an N₂ atmosphereat 80° C. for 19 h. Purification via reverse phase HPLC using 10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

Method B

A solution of mesylate (1 equivalent), triethylamine (3 equivalents),amine (2-5 equivalents) in DMF (0.3-0.5 M) was stirred under an N₂atmosphere at RT for 19 h. Purification via reverse phase HPLC using10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

Method C

A solution of mesylate (1 equivalent), potassium fluoride (1equivalent), amine (2-5 equivalent) in acetonitrile (0.3-0.5 M) wasmicrowaved at 150° C. for 10 min. Purification via reverse phase HPLCusing 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

4-(3-(2-Chlorophenoxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 54, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=450; t_(R)=1.58 min.

4-(3-(3-Chlorophenylamino)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 54, method C. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=449; t_(R)=1.51 min.

(S)-4-(3-(4-Methylpiperidin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 54, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=421.8; t_(R)=0.88 min.

(S)-4-(3-(6-Chlorobenzo[d]thiazol-2-ylamino)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 54, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=506.2; t_(R)=1.56 min.

4-(3-(2-Chloro-6-methylbenzylamino)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 54, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=477; t_(R)=1.04 min.

4-(3-(2,6-Dichlorophenethylamino)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 54, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=511; t_(R)=1.12 min.

General Procedure 55

Under an N₂ atmosphere at −20° C., DMAP (1.5-3 equivalent) was added toa solution of alcohol (1 equivalent) in CH₂Cl₂ (0.5 M). To the reactionmixture then added triethylamine (3 equivalents). P-toluenesulfonicanhydride (3 equivalents) was added dropwise to this solution at −20° C.Upon completion of addition, the mixture was stirred at RT overnight.The reaction mixture was poured into water and extracted with CH₂Cl₂(2×), dried over magnesium sulfate, and concentrated. Purification viasilica gel chromatography using 2-10% MeOH in CH₂Cl₂ gave bis tosylatedalcohol. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=648.5; t_(R)=1.92 min.

General Procedure 56

A solution of tosylated alcohol (1 equivalent), triethylamine (4equivalents), amine (4 equivalents) in DMF (0.3-0.5 M) was stirred underN₂ atmosphere at 60° C. for 19 h. Purification via reverse phase HPLCusing 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

(S)-4-(3-(4-(4-Chlorophenyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 56. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=517.3; t_(R)=1.28 min.

(S)-4-(3-(4-(3,5-Dichlorophenyl)piperazin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 56. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=552; t_(R)=1.35 min.

4-(3S)-3-(3-((3,5-Dichlorophenyl)morpholino)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 56. LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=553; t_(R)=1.29 min.

Route 3 General Procedure 57

Under an N₂ atmosphere at −20° C., N,N-diisopropylethylamine (3 eq) wasadded dropwise to a solution of solution of(R)-(+)α-hydroxy-γ-butyrolactone (1 eq) in dichloromethane (0.5 mL).Then added trifluoromethanesulfonic anhydride (1-1.2 eq) dropwise bymaintaining internal temperature of the reaction mixture <−20° C. Uponcompletion of addition, the mixture was stirred at −20° C. for 1 hour.Then added at −20° C., amine (1.5 eq) dropwise. The reaction was allowedto warm to RT over a period of 30 minutes and continued to stir at RTfor 16 hrs. The reaction mixture was diluted with 200 mL of ethylacetateand washed with saturated sodium bicarbonate (3×). The organic layer waswashed with a saturated aqueous NaCl solution (2×). The solution wasdried over magnesium sulfate, filtered, and concentrated. Purificationvia silica gel chromatography using 10-30% ethyl acetate in hexane gavedesired product.

General Procedure 58

To a solution of sulfathiazole (1-1.2 eq.) in CH₂Cl₂ (0.5 M) undernitrogen at RT was added a solution of trimethylaluminum in hexane(2.0M, 1-1.2 eq.) over 5 min. After stirring at RT for 20 min, asolution of the lactone (1 eq.) in CH₂Cl₂ (0.4 M) was added over 10 min.Stirring was continued for 18-36 h at RT or reflux, then the reactionmixture was cooled to 0° C. and quenched by careful addition of aqueous1M HCl. Phases were separated, and the aqueous phase was extracted withCH₂Cl₂ (2×). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via silica gel chromatography using 2-10%MeOH in CH₂Cl₂ gave the desired products.

General Procedure 59

To a yellow solution of di-tert-butyl azo-dicarboxylate (2-4 eq.) in THF(0.4 M) at 0° C. under N₂ was slowly added tributylphosphine (2-4 eq.),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (1 eq.)in THF (0.3 M) at 0° C. under N₂. The reaction mixture was stirred for10 min. at this temperature, and quenched by addition of a saturatedaqueous NaHCO₃ solution. EtOAc was added, the phases were separated, andthe aqueous layer was extracted with EtOAc (2×). The combined organicextracts were dried over MgSO₄ and concentrated. Purification via silicagel chromatography using EtOAc in hexane gave the desired products.

(S)-3-(4-Chloroindolin-1-yl)dihydrofuran-2(3H)-one

Prepared using general procedure 57. Under an N₂ atmosphere at −20° C.,diisopropyl ethyl amine (7.59 g, 10.23 mL, 58.77 mmol) was added dropwise to a solution of solution of (R)-3-hydroxydihydrofuran-2(3H)-one (3g, 29.38 mmol) in dichloromethane (50 mL). Then addedtrifluoromethanesulfonic anhydride (8.69 g, 5.18 mL, 30.81 mmol) dropwise by maintaining internal temperature of the reaction mixture <−20°C. Upon completion of addition, the mixture was stirred at −20° C. for 1hour. Then added at −20° C., 4-chloro-indoline (6.74 gm, 44.07 mmol)drop wise. The reaction was allowed to warm to RT over a period of 30minutes and continued to stir at RT for 16 hrs. The reaction mixture wasdiluted with 200 mL of ethylacetate and washed with saturated sodiumbicarbonate (3×50 mL). The organic layer was washed with a saturatedaqueous NaCl solution (2×50 mL). The solution was dried over magnesiumsulfate, filtered, and concentrated. Purification via silica gelchromatography using 10-30% ethyl acetate in hexane gave(S)-3-(4-chloroindolin-1-yl)dihydrofuran-2(3H)-one as a white solid(5.47 g, 80% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.03 (t, J=8.0 Hz, 1H),6.63 (dd, J=0.6, 8.0 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 4.91 (dd, J=9.2,11.2 Hz, 1H), 4.45-4.40 (m, 1H), 4.30-4.23 (m, 1H), 3.55-3.48 (m, 1H),3.28 (dd, J=8.5, 18.0 Hz, 1H), 2.99-2.94 (m, 2H), 2.40-2.32 (m, 2H).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=237.9;t_(R)=1.51 min.

(S)-2-(4-Chloroindolin-1-yl)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide

Prepared using general procedure 58. Under an N₂ atmosphere at RT,2M-trimethyl aluminium in hexane (9.13 mL) was added dropwise to astirring solution of sulfathiazole (4.6 g, 18.27 mmol) indichloromethane (100 mL) in 30 minutes. Upon completion of addition, themixture was stirred at RT for an hour. Added(S)-3-(4-chloroindolin-1-yl)dihydrofuran-2(3H)-one (3.56 g, 14.97 mmol)in dichloromethane (20 mL) to above solution over 30 minutes. Themixture was stirred for 16 hrs at RT. The reaction mixture was dilutedwith 500 mL of ethylacetate were added. The aqueous phase was acidifiedto pH 2 with an (1N) aqueous HCl solution. The ethyl acetate layer waswashed with (1N) aqueous HCl (3×200 mL) till LCMS showed disappearanceof sulfathiazole. The organic layer was dried over MgSO₄, filtered,concentrated. Purification via silica gel chromatography using 2-10%methanol in dichloromethane gave the amide as a white solid (5.9 g, 80%yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=493.2; t_(R)=1.46 min. ¹H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 7.74(s, 4H), 7.24 (d, J=4.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 6.81 (d, J=4.5Hz, 1H), 6.56-6.54 (m, 2H), 4.71 (t, J=4.8 Hz, 1H), 4.43-4.39 (m, 1H),3.79 (q, J=9.3 Hz, 1H), 3.64-3.58 (m, 2H), 3.51-3.48 (m, 1H), 3.17 (d,J=5.2 Hz, 1H), 3.00-2.89 (m, 1H), 1.93 (dd, J=6.0, 13.5 Hz, 1H), 1.88(s, 1H).

(S)-4-(3-(4-Chloroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 59. To a cooled (0° C.) solution ofdi-tert-butyl azo-dicarboxylate (3.73 g, 16.2 mmol) in THF (20 mL), wasadded drop wise tributyl phosphine (3.27 g, 4.0 mL, 16.2 mmol). Uponcompletion of addition, the mixture was stirred at 0° C. for 1 hour. Tothis solution was added(S)-4-(3-(4-chloroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(2.0 g, 4.1 mmol) in dichloromethane (10 mL) dropwise over a 10 minuteperiod at 0° C. Upon completion of addition, the mixture was stirred at0° C. for 1 hour. The mixture was poured into cold water (35 mL), andextracted with EtOAc (3×100 mL). The organic portion was dried overmagnesium sulfate, filtered, and concentrated. The residue was purifiedvia silica gel chromatography using CH₂Cl₂ to gave the lactam as a whitesolid (700 mg, 35% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=475.2; t_(R)=1.65 min, ¹H NMR (400 MHz, DMSO) δ12.74 (s, 1H), 7.82 (m, 4H), 7.26 (d, J=4.6 Hz, 1H), 7.00 (t, J=8.0 Hz,1H), 6.83 (d, J=4.6 Hz, 1H), 6.59 (d, J=7.9 Hz, 1H), 6.50 (d, J=7.9 Hz,1H), 4.82 (dd, J=8.8, 10.8 Hz, 1H), 3.91-3.81 (m, 2H), 3.62-3.55 (m,1H), 3.49-3.38 (m, 1H), 3.02-2.95 (m, 2H), 2.40-2.33 (m, 1H), 2.20-2.15(m, 1H).

(S)-3-(6-Chloro-3,4-dihyroquinolin-1(2H)-yl)dihyrofuran-2(3H)-one

Prepared using general procedure 57. Under an N₂ atmosphere at −20° C.,diisopropyl ethyl amine (15.9 mL, 91.4 mmol) was added drop wise to asolution of solution of (R)-3-hydroxydihydrofuran-2(3H)-one (4.67 g,45.7 mmol) in dichloromethane (70 mL). Then addedtrifluoromethanesulfonic anhydride (8.1 mL, 48.0 mmol) drop wise bymaintaining internal temperature of the reaction mixture <−20° C. Uponcompletion of addition, the mixture was stirred at −20° C. for 1 hour.Then added at −20° C., 6-chloro-1,2,3,4-tetrahydroquinoline drop wise.The reaction was allowed to warm to RT over a period of 30 minutes andcontinued to stir at RT for 16 hrs. The reaction mixture was dilutedwith 200 mL of ethylacetate and washed with saturated sodium bicarbonate(3×50 mL). The organic layer was washed with a saturated aqueous NaClsolution (2×50 mL). The solution was dried over magnesium sulfate,filtered, and concentrated. Purification via silica gel chromatographyusing 5-50% ethyl acetate in hexane gave(S)-3-(6-chloro-3,4-dihyroquinolin-1(2H)-yl)dihyrofuran-2(3H)-one as awhite solid (10.74 g, 93% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=252.3; t_(R)=1.66 min. ¹H NMR (400 MHz,DMSO-d6) δ 7.03-6.98 (m, 2H), 6.74 (d, J=8.9 Hz, 1H), 5.07 (t, J=10.0Hz, 1H), 4.42 (t, J=9.5 Hz, 1H), 4.30-4.23 (m, 1H), 3.16-3.02 (m, 2H),2.68 (t, J=6.4 Hz, 2H), 2.44-2.27 (m, 2H), 1.87-1.77 (m, 2H).

(S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide

Prepared using general procedure 58. Under an N₂ atmosphere at RT,2M-trimethylaluminium in hexane (19.2 mL, 38.4 mmol) was added drop wiseto a stirring solution of sulfathiazole (9.81 g, 38.4 mmol) indichloromethane (90 mL) in 30 minutes. Upon completion of addition, themixture was stirred at RT for an hour. Added(S)-3-(6-chloro-3,4-dihyroquinolin-1-(2H)-yl)dihydrofuran-2-(3H)-one(10.7 g, 42.7 mol) in dichloromethane (90 mL) to above solution over 30minutes. The mixture was stirred for 16 hrs at RT. The reaction mixturewas diluted with 500 mL of ethylacetate were added. The aqueous phasewas acidified to pH 2 with an (1N) aqueous HCl solution. The ethylacetate layer was washed with (1N) aqueous HCl (3×200 mL) till LCMSshowed disappearance of sulfathiazole. The organic layer was dried overMgSO₄, filtered, concentrated. Purification via silica gelchromatography using 2-10% methanol in dichloromethane gave the(S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide as a white solid (5.73 g, 30% yield). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=507.3; t_(R)=1.53 min. ¹HNMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.78 (s, 4H), 7.24 (d, J=4.6 Hz,1H), 7.01-6.96 (m, 2H), 6.82-6.76 (m, 2H), 4.68 (s, 1H), 4.59 (t, J=7.1Hz, 1H), 4.03 (dd, J=14.2, 7.1 Hz, 1H), 3.47 (s, 2H), 3.35-3.21 (m, 2H),2.69 (t, J=6.0 Hz, 2H), 2.14-2.06 (m, 1H), 1.93-1.78 (m, 2H).

(S)-4-(3-(6-Chloro-3,4-dihydroquinolin-(2H)l-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 59. To a cooled (0° C.) solution ofdi-tert-butyl azodicarboxylate (0.937 g, 4.07 mmol) in THF (5 mL), wasadded drop wise tributyl phosphine (0.823 g, 1.01 mL, 4.07 mmol). Uponcompletion of addition, the mixture was stirred at 0° C. for 1 hour. Tothis solution was added(S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide(0.53 g, 1.01 mmol) in dichloromethane (10 mL) drop wise over a 10minute period at 0° C. Upon completion of addition, the mixture wasstirred at 0° C. for 1 hour. The mixture was poured into cold water (35mL), and extracted with EtOAc (3×100 mL). The organic portion was driedover magnesium sulfate, filtered, and concentrated. The residue waspurified via silica gel chromatography using CH₂Cl₂ to give(S)-4-(3-(6-chloro-3,4-dihydroquinolin-(2H)l-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamideas a white solid (222 mg, 45% yield). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=489.5; t_(R)=1.77 min. ¹H NMR (400MHz, DMSO-d6) δ 12.74 (s, 1H), 7.85 (dd, J=23.1, 9.0 Hz, 4H), 7.26 (d,J=4.6 Hz, 1H), 7.00 (s, 1H), 6.98 (s, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.75(d, J=9.2 Hz, 1H), 5.00 (t, J=9.6 Hz, 1H), 3.90-3.79 (m, 2H), 3.16 (t,J=5.8 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 2.43-2.36 (m, 2H), 2.18-2.08 (m,2H).

Route 4 (S)-3-(4-Chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one

Prepared using general procedure 57. Under an N₂ atmosphere at −40° C.,N,N-diisopropylethylamine (34.1 mL, 196 mmol) was added dropwise to asolution of solution of (R)-dihydro-3-hydroxyfuran-2(3H)-one (10.0 g, 98mmol) in CH₂Cl₂ (100 mL). Trifluoromethanesulfonic anhydride (17.3 mL,103 mmol) was added dropwise to this solution maintaining the internaltemperature of the reaction mixture below −40° C. Upon completion ofaddition, the mixture was stirred at −40° C. for 1 h. A solution of4-chloro-5-fluoroindoline (27.6, 147 mmol) in CH₂Cl₂ (40 mL) was addeddropwise to this solution maintaining the internal temperature of thereaction mixture below −40° C. The reaction was allowed to warm up to−20° C. and was kept at this temperature for 48 h. The reaction mixturewas washed with saturated aqueous sodium bicarbonate (2×), brine, driedover magnesium sulfate, and concentrated. Purification via silica gelchromatography using 0-40% ethyl acetate in hexane gave(S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one as a whitesolid (22.9 g, 90%). ¹H NMR (400 MHz, DMSO-d6) δ 7.07-7.02 (m, 1H), 6.50(dd, J=3.6, 8.6 Hz, 1H), 4.88 (dd, J=9.0, 11.4 Hz, 1H), 4.44-4.39 (m,1H), 4.29-4.22 (m, 1H), 3.60-3.54 (m, 1H), 3.28 (dd, J=8.6, 17.8 Hz,1H), 3.07-2.92 (m, 2H), 2.43-2.28 (m, 2H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=256.1; t_(R)=1.54 min.

General Procedure 60

To a solution of aniline (1-1.2 eq.) in CH₂Cl₂ (0.5 M) under nitrogen atRT was added a solution of trimethylaluminum in hexane (2.0M, 1-1.2 eq.)over 5 min. After stirring at RT for 20 min, a solution of the lactone(1 eq.) in CH₂Cl₂ (0.4 M) was added over 10 min. Stirring was continuedfor 18-36 h at RT or reflux, then the reaction mixture was cooled to 0°C. and quenched by careful addition of aqueous 1M HCl. Phases wereseparated, and the aqueous phase was extracted with CH₂Cl₂ (2×). Thecombined organic extracts were dried over MgSO₄ and concentrated.Purification via silica gel chromatography using 2-10% MeOH in CH₂Cl₂gave the desired products.

(S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-phenylbutanamide

Prepared using general procedure 60: To a solution of aniline (1.0 mL,11.1 mmol) in CH₂Cl₂ (25 mL) under nitrogen at RT was added a solutionof trimethylaluminum in hexane (2.0 M, 5.5 mL, 11.0 mmol) over 5 min.After stirring at RT for 20 min, a solution of(S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-dihydrofuran-2(3H)-one(2.32 g, 9.2 mmol) in CH₂Cl₂ (25 mL) was added over 10 min. Stirring wascontinued for 18 h at RT, then the reaction mixture was cooled to 0° C.and quenched by careful addition of aqueous 1M HCl (25 mL). Phases wereseparated, and the aqueous phase was extracted with CH₂Cl₂ (2×50 mL).The combined organic extracts were dried over MgSO₄ and concentrated.Purification via silica gel chromatography using 2-10% MeOH in CH₂Cl₂gave(S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-phenylbutanamideas a white solid (2.56 g, 81%). ¹H NMR (400 MHz, DMSO-d6) δ 10.00 (s,1H), 7.60 (dd, J=1.0, 8.5 Hz, 2H), 7.29 (dd, J=1.8, 14.1 Hz, 2H),7.07-6.95 (m, 3H), 6.80 (d, J=9.0 Hz, 1H), 4.67 (t, J=4.9 Hz, 1H), 4.56(t, J=7.2 Hz, 1H), 3.47 (dd, J=6.1, 11.2 Hz, 2H), 3.39-3.34 (m, 1H),3.31-3.25 (m, 1H), 2.71-2.68 (m, 2H), 2.15-2.04 (m, 1H), 1.94-1.80 (m,3H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=345.3; t_(R)=3.44 min.

(S)-2-(4-Chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide

Prepared using general procedure 60: To a solution of aniline (1.4 mL,15.6 mmol) in CH₂Cl₂ (37 mL) under nitrogen at RT was added a solutionof trimethylaluminum in hexane (2.0 M, 7.8 mL, 15.6 mmol) over 5 min.After stirring at RT for 20 min, a solution of(S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one (4.0 g,15.6 mmol) in CH₂Cl₂ (37 mL) was added over 10 min. Heated to reflux for12 h, then the reaction mixture was cooled to 0° C. and quenched bycareful addition of aqueous 1M HCl (70 mL). Phases were separated, andthe aqueous phase was extracted with CH₂Cl₂ (2×75 L). The combinedorganic extracts were dried over MgSO₄ and concentrated. Purificationvia silica gel chromatography using 2-7.5% MeOH in CH₂Cl₂ gave(S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide as awhite solid (5.44 g, 100%). ¹H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H),7.59 (d, J=7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.07-6.99 (m, 2H), 6.53 (dd,J=3.6, 8.6 Hz, 1H), 4.70 (t, J=4.9 Hz, 1H), 4.35 (t, J=7.4 Hz, 1H),3.92-3.80 (m, 1H), 3.68-3.62 (m, 1H), 3.55-3.47 (m, 2H), 3.05-2.89 (m,2H), 2.12-2.01 (m, 1H), 1.98-1.88 (m, 1H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=349.1; t_(R)=1.69 min.

General Procedure 61

To a yellow solution of di-tert-butyl azo-dicarboxylate (2-4 eq.) in THF(0.4 M) at 0° C. under N₂ was slowly added tributylphosphine (2-4 eq.),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (1 eq.)in THF (0.3 M) at 0° C. under N₂. The reaction mixture was stirred for10 min. at this temperature, and quenched by addition of a saturatedaqueous NaHCO₃ solution. EtOAc was added, the phases were separated, andthe aqueous layer was extracted with EtOAc (2×). The combined organicextracts were dried over MgSO₄ and concentrated. Purification via silicagel chromatography using EtOAc in hexane gave the desired products.

(S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-1-phenylpyrrolidin-2-one

Prepared using general procedure 61: To a yellow solution ofdi-tert-butyl azo-dicarboxylate (2.23 g, 9.7 mmol) in THF (25 mL) at 0°C. under N₂ was slowly added tributylphosphine (2.4 mL, 9.7 mmol), Theresulting colorless solution of the Mitsunobu reagent was stirred at RTfor 10 min, and then added to a solution of(S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-phenylbutanamide(2.56 g, 7.4 mmol) in THF (25 mL) at 0° C. under N₂. The reactionmixture was stirred for 10 min. at this temperature, and quenched byaddition of a saturated aqueous NaHCO₃ solution. EtOAc was added, thephases were separated, and the aqueous layer was extracted with EtOAc(2×). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via silica gel chromatography using 20-40EtOAc in hexane gave(S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-phenylpyrrolidin-2-oneas a white solid (2.43 g, 100%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=327.5; t_(R)=1.50 min.

(S)-3-(4-Chloro-5-fluoroindolin-1-yl)-1-phenylpyrrolidin-2-one

Prepared using general procedure 61: To a yellow solution ofdi-tert-butyl azo-dicarboxylate (2.72 g, 11.9 mmol) in THF (14 mL) at 0°C. under N₂ was slowly added tributylphosphine (3.0 mL, 11.9 mmol), Theresulting colorless solution of the Mitsunobu reagent was stirred at RTfor 10 min, and then added to a solution of(S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide (1.03g, 7.4 mmol) in THF (14 mL) at 0° C. under N₂. The reaction mixture wasstirred for 10 min. at this temperature, and quenched by addition of asaturated aqueous NaHCO₃ solution. EtOAc was added, the phases wereseparated, and the aqueous layer was extracted with EtOAc (2×). Thecombined organic extracts were dried over MgSO₄ and concentrated.Purification via silica gel chromatography using 0-50 EtOAc in hexanegave (S)-3-(4-chloro-5-fluoroindolin-1-yl)-1-phenylpyrrolidin-2-one as awhite solid (2.1 g, 82%). ¹H NMR (400 MHz, DMSO-d6) δ 7.71-7.68 (m, 2H),7.42-7.38 (m, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.04-6.99 (m, 1H), 6.49 (dd,J=3.6, 8.7 Hz, 1H), 4.77 (dd, J=8.8, 10.6 Hz, 1H), 3.85-3.81 (m, 2H),3.62 (dd, J=2.7, 8.9 Hz, 1H), 3.40 (dd, J=8.6, 17.9 Hz, 1H), 3.05-2.95(m, 2H), 2.40-2.31 (m, 1H), 2.21-2.10 (m, 1H). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=331.5; t_(R)=1.90 min.

General Procedure 62

To chlorosulfonic acid (5-30 eq.) at 0° C. under N₂ was added thephenyl-pyrrolidin-2-one (1 eq.) in portions. The reaction mixture washeated to 50-60° C. for 15-20 min. and, after cooling to RT, carefullypoured onto ice-water. EtOAc or CH₂Cl₂ were added, the phases wereseparated, and the aqueous layer was extracted with EtOAc or CH₂Cl₂(2×). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via silica gel chromatography using EtOAc inhexane gave the desired products.

4-((S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)benzene-1-sulfonylchloride

Prepared using general procedure 62: To chlorosulfonic acid (15 mL, 220mmol) at 0° C. under N₂ was added(S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-phenylpyrrolidin-2-one(2.43 g, 7.4 mmol) in portions. The reaction mixture was heated to 50°C. for 15 min. and, after cooling to RT, carefully poured onto ice-water(500 mL). EtOAc (150 mL) was added, the phases were separated, and theaqueous layer was extracted with EtOAc (2×150 mL). The combined organicextracts were dried over MgSO₄ and concentrated. Purification via silicagel chromatography using 50-80% EtOAc in hexane gave4-((S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-benzene-1-sulfonylchloride as an off-white solid (1.92 g, 61%). ¹H NMR (400 MHz, DMSO-d6)δ 7.66 (dd, J=2.1, 6.8 Hz, 2H), 7.61 (dd, J=2.1, 6.8 Hz, 2H), 6.99 (d,J=9.0 Hz, 2H), 6.77 (d, J=8.7 Hz, 1H), 5.01-4.96 (m, 1H), 3.85-3.81 (m,2H), 3.17 (t, J=5.6 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 2.42-2.32 (m, 1H),2.15-2.08 (m, 1H), 1.92-1.79 (m, 2H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=425.1; t_(R)=4.03 min

4-((S)-3-(4-Chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)benzene-1-sulfonylchloride

Prepared using general procedure 62: To chlorosulfonic acid (2.0 mL) at0° C. under N₂ was added(S)-3-(4-chloro-5-fluoroindolin-1-yl)-1-phenylpyrrolidin-2-one (1.92 g,5.8 mmol) in portions. The reaction mixture was heated to 60° C. for 20min. and, after cooling to RT, carefully poured onto ice-water. EtOAcwas added, the phases were separated, and the aqueous layer wasextracted with EtOAc (2×). The combined organic extracts were dried overMgSO₄ and concentrated to give4-((S)-3-(4-chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)benzene-1-sulfonylchloride which was used without further purification. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=429.3; t_(R)=2.14 min.

General Procedure 63

Method A

A solution of the sulfonyl chloride (1 eq.),2-tert-butyl-1,1,3,3-tetramethylguanidine (5 eq.), and amine (1 eq.) inacetonitrile (0.3-0.5 M) was stirred under an N₂ atmosphere at RT for 19h. Purification via reverse phase HPLC using 10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA) gave the desired products.

Method B

A solution of the sulfonyl chloride (1 eq.), DABCO (5 eq.), and amine (1eq.) in acetonitrile (0.3-0.5 M) was stirred under an N₂ atmosphere atRT for 19 h. Purification via reverse phase HPLC using 10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

Method C

A solution of the sulfonyl chloride (1 eq.), and amine (1 eq.) inpyridine (0.3-0.5 M) was stirred under an N₂ atmosphere at RT for 19 h.Purification via reverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA) gave the desired product.

Method D

A solution of the sulfonyl chloride (1 eq.), phosphazene baseP1-t-Bu-tris(tetramethylene) (5 eq.), and amine (1 eq.) in acetonitrile(0.3-0.5 M) was stirred under an N₂ atmosphere at RT for 19 h.Purification via reverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA) gave the desired product.

4-((S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Synthesized according to general procedure 63, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=490.3; t_(R)=3.47 min

4-((S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(pyrimidine-4-yl)benzenesulfonamide

Synthesized according to general procedure 63, method B. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=484.5; t_(R)=3.11 min

4-((S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 63, method C. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=489.3; t_(R)=3.36 min.

4-((S)-3-(4-Chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(5-methyl-thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 63, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=507; t_(R)=1.75 min.

4-((S)-3-(4-Chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 63, method A. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=494.3; t_(R)=1.68 min.

4-((S)-3-(4-Chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(6-chloropyradazin-2-yl)benzenesulfonamide

Synthesized according to general procedure 63, method D. LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=522; t_(R)=1.83 min.

Route 5 (R)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)pyrrolidin-2-one

Prepared using general procedure 57. Under an N₂ atmosphere at −20° C.,N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) was added dropwise to asolution of (S)-3-hydroxypyrrolidin-2-one (500 mg, 5.0 mmol) in CH₂Cl₂(8 mL). Trifluoromethanesulfonic anhydride (0.88 mL, 5.25 mmol) wasadded dropwise to this solution. Upon completion of addition, themixture was stirred at −20° C. for 30 min.6-Chloro-1,2,3,4-tetrahydroquinoline (1.26 g, 7.5 mmol) was added in oneportion. The reaction was allowed to warm up to RT overnight. After 18h, the reaction mixture was washed with saturated aqueous sodiumbicarbonate (2×20 mL), brine (20 mL), dried over magnesium sulfate, andconcentrated. Purification via silica gel chromatography using 0-30%ethyl acetate in hexane gave(R)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)pyrrolidin-2-one as acolorless oil (150 mg, 12%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=251.3; t_(R)=2.77 min.

General Procedure 64

4-Bromo-benzenesulfonamide (1 eq.), pyrrolidin-2-one (1.2 eq.), copper(I) iodide (10 mol %), N,N′-dimethylethylenediamine (20 mol %), andK₂CO₃ (4 eq.) were combined in a microwave vial and set under nitrogen.NMP (0.4 M) was added, and the reaction mixture was heated to 200° C.for 30 min. using microwave irradiation. After cooling to RT, thereaction mixture was diluted with DMSO/MeOH (1:1) and purified viareverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) togive the desired products.

(R)-4-(3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Prepared using general procedure 64.4-Bromo-N-(thiazol-2-yl)benzenesulfonamide (54 mg, 0.17 mmol),(R)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)pyrrolidin-2-one (50 mg,0.20 mmol), copper(I) iodide (3.8 mg, 10 mol %),N,N′-dimethylethylenediamine (4.2 μL, 20 mol %), and K₂CO₃ (94 mg, 0.68mmol) were combined in a microwave vial and set under nitrogen. NMP (0.4mL) was added, and the reaction mixture was heated to 200° C. for 30min. using microwave irradiation. After cooling to RT, the reactionmixture was diluted with DMSO/MeOH (1:1, 0.6 mL) and purified viareverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) togive(R)-4-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide.LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=489.3;t_(R)=3.27 min.

(S)-4-(3-(1H-Indol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

A suspension of(S)-4-(3-(indolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)-benzenesulfonamide(10 mg, 0.023 mmol) and activated MnO₂ (20 mg, 0.23 mmol) in CH₂Cl₂ (1.0mL) was heated to 50° C. for 20 h. After cooling to RT, the reactionmixture was filtered through a syringe filter, concentrated anddissolved in DMSO/MeOH (1:1, 0.8 mL). Purification via reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave(S)-4-(3-(1H-Indol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide.¹H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=2.1 Hz, 2H), 7.82 (d, J=3.0 Hz,2H), 7.47 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.19 (d, J=3.3 Hz,1H), 7.08-7.03 (m, 1H), 7.01-6.94 (m, 2H), 6.62 (d, J=4.7 Hz, 1H), 6.44(d, J=3.2 Hz, 1H), 5.51 (dd, J=8.9, 10.9 Hz, 1H), 4.02-3.98 (m, 2H),2.72-2.68 (m, 1H), 2.49-2.40 (m, 1H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=439.2; t_(R)=2.99 min.

(S)-4-(3-(5-chloro-1H-indol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

A suspension of(S)-4-(3-(5-chloroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(11 mg, 0.023 mmol) and activated MnO₂ (20 mg, 0.23 mmol) in CH₂Cl₂ (1.0mL) was heated to 50° C. for 20 h. After cooling to RT, the reactionmixture was filtered through a syringe filter, concentrated anddissolved in DMSO/MeOH (1:1, 0.8 mL). Purification via reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave(S)-4-(3-(5-chloro-1H-indol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide.¹H NMR (400 MHz, MeOD-d4) δ 7.83 (d, J=3.8 Hz, 2H), 7.81 (d, J=2.5 Hz,2H), 7.46 (d, J=2.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.04-6.99 (m, 2H), 6.62(d, J=4.7 Hz, 1H), 6.43 (d, J=3.2 Hz, 1H), 5.51 (dd, J=8.9, 11.0 Hz,1H), 3.99 (dd, J=6.1, 9.7 Hz, 2H), 2.75-2.67 (m, 1H), 2.48-2.38 (m, 1H).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=473.2;t_(R)=3.21 min.

Route 6 (R)—S-Ethyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate

To a stirring suspension of(R)-(−)-dimethyl-5-oxo-1,2-dioxolane-4-acetic acid (3.5 g, 20 mmol), andCH₂Cl₂ (40 mL), at 0° C., under N₂, was added isovalerylchloroformate(2.9 mL, 22 mmol) dropwise over 5 minutes. The mixture was stirred at 0°C. for 10 minutes. Triethylamine (5.5 mL, 40 mmol) was added dropwise at0° C. followed by the dropwise addition of ethanethiol (3.4 mL, 44mmol). The pink mixture was stirred at 0° C. for 10 minutes. To thereaction was added Et₂O (40 mL) and the mixture was filtered. Thefiltrate was washed with 1.0 N aqueous HCl (20 mL), 0.1 N aqueous NaOH(20 mL), H₂O (20 mL) and brine (20 mL). The organic solution wasevaporated to dryness under reduced pressure to obtain the desiredthioester as a clear oil (3.4 g, 16 mmol, 82% yield). ¹H NMR (400 MHz,CDCl₃) δ 4.71-4.65 (m, 1H), 3.91-3.81 (m, 1H), 3.11-2.70 (m, 3H), 1.53(s, 3H), 1.50 (s, 3H), 0.87-0.86 (m, 3H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=219.4; t_(R)=1.33 min.

General Procedure 65

To a stirring mixture of (R)—S-ethyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (1 equivalent),10% palladium on carbon (470 mg), and CH₂Cl₂ (0.5-1 M) under N₂, at 25°C., was added triethylsilane (1.5 equivalent) dropwise over 10 minutes.The mixture was stirred at 25° C. for 1 hour. The mixture was filteredand the filtrate was evaporated to dryness under reduced pressure togive the desired aldehyde as clear oil. The aldehyde was added to astirring mixture of sulfathiazole (0.5 equivalent), MeOH (1 M), andtrifluoroacetic acid (0.1 M). To this solution was added sodiumborohydride (2.5 equivalent) portionwise over 10 minutes. The mixturewas stirred for 10 minutes and evaporated under reduced pressure. Theresidue was purified via silica gel chromatography using 5% MeOH inCH₂Cl₂ to obtain the desired amine.

(R)-4-(2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)ethylamino)-N-(thiazol-2-yl)benzenesulfonamide

Synthesised according to general procedure 65. To a stirring mixture of(R)—S-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (1.9g, 8.7 mmol), 10% palladium on carbon (470 mg), and CH₂Cl₂ (20 mL) underN₂, at 25° C., was added triethylsilane (2.08 mL, 13.0 mmol) dropwiseover 10 minutes. The mixture was stirred at 25° C. for 1 hour. Themixture was filtered and the filtrate was evaporated to dryness underreduced pressure to give the desired aldehyde as a clear oil (1.2 g).The aldehyde was added to a stirring mixture of sulfathiazole (1.1 g,4.3 mmol), MeOH (25 mL), and trifluoroacetic acid (2.5 mL). To thissolution was added sodium borohydride (813 mg, 21.4 mmol) portionwiseover 10 minutes. The mixture was stirred for 10 minutes and evaporatedunder reduced pressure. The residue was purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ to obtain the desired amine as awhite solid (1.5 g, 3.9 mmol, 45% yield). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=398.3; t_(R)=1.18 min.

General Procedure 66

A stirring solution of benzenesulfonamide (1 equivalent),p-toluenesulfonic acid monohydrate (0.1 equivalent), and THF (0.5-1 M)was stirred at 80° C. for 3 hours. The mixture was concentrated todryness under reduced pressure. The residue was purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ to give the desired lactam.

(R)-4-(3-Hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesised according to general procedure 66. A stirring solution of(R)-4-(2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethylamino)-N-(thiazol-2-yl)benzenesulfonamide(833 mg, 2.15 mmol), p-toluenesulfonic acid monohydrate (42 mg g, 0.22mmol), and THF (10 mL) was stirred at 80° C. for 3 hours. The mixturewas concentrated to dryness under reduced pressure. The residue waspurified via silica gel chromatography using 5% MeOH in CH₂Cl₂ to givethe desired lactam as a white solid (496 g, 1.4 mmol, 65% yield). ¹H NMR(400 MHz, DMSO-d6) δ 7.85 (dd, J=2.1, 6.9 Hz, 4H), 7.25 (d, J=4.6 Hz,1H), 6.82 (d, J=4.6 Hz, 1H), 5.83 (d, J=5.9 Hz, 1H), 4.32 (d, J=5.3 Hz,1H), 3.77 (dd, J=1.9, 9.0 Hz, 1H), 3.71-3.69 (m, 1H), 2.41-2.38 (m, 1H),1.84 (dd, J=9.2, 12.3 Hz, 1H).). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=340.2; t_(R)=0.50 min.

General Procedure 67

To a stirring suspension of N-benzenesulfonamide (1 equivalent) inCH₂Cl₂ (0.5-1 M), under N₂, at 0° C., was addedN,N-diisopropylethylamine (1 equivalent) followed by allylbromide (1equivalent). The mixture was stirred at ambient temperature for 19hours. The mixture was evaporated to dryness under reduced pressure. Theresidue was purified via silica gel using 50% EtOAc in hexanes to givethe desired sulfonamide.

(R)—N-Allyl-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesised according to general procedure 67. To a stirring suspensionof(R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(200 mg, 0.59 mmol) in CH₂Cl₂ (0.50 mL), under N₂, at 0° C., was addedN,N-diisopropylethylamine (0.10 mL, 0.59 mmol) followed by allylbromide(51 uL, 0.59 mmol). The mixture was stirred at ambient temperature for19 hours. The mixture was evaporated to dryness under reduced pressure.The residue was purified via silica gel using 50% EtOAc in hexanes togive the desired sulfonamide as a white solid (220 mg, 0.57 mmol, 96%yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37 (d, J=4.7Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd, J=1.3,10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz, 2H),4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H),2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).

(S)—N-Allyl-4-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 49. The reaction was set upwith(R)—N-allyl-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(100 mg, 0.26 mmol) triflic anhydride (51 uL, 0.29 mmol),N,N-diisopropylethylamine (90 uL, 0.52 mmol), CH₂Cl₂, and6-chloro-1,2,3,4-tetrahydroquinoline (65 mg, 0.39 mmol). The reactionwas held at −25° C. for 19 hours and quenched with H₂O (30 uL). Theresidue was purified via silica gel using 10% MeOH in CH₂Cl₂ to obtainthe desired lactam as a white solid (102 g, 0.19 mmol, 73% yield). ¹HNMR (400 MHz, DMSO-d6) δ 7.87 (m, 4H), 7.37 (d, J=4.7 Hz, 1H), 7.99-7.95(m, 3H), 6.93 (d, J=4.7 Hz, 1H), 6.75 (d, J=9.1 Hz, 1H), 5.92-5.82 (m,1H), 5.17 (dd, J=1.3, 10.3 Hz, 1H), 5.01-4.97 (m, 2H), 4.56-4.55 (m,2H), 3.89-3.79 (m, 2H), 3.42-3.23 (m, 1H), 3.20-3.11 (m, 2H), 2.70 (t,J=6.3 Hz, 2H), 2.42-2.33 (m, 1H), 2.17 (d, J=9.7 Hz, 1H), 1.93-1.76 (m,2H).

(S)-4-(3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 50. The reaction was set upwith(S)—N-allyl-4-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(100 mg, 0.19 mmol), CH₃CN (1.5 mL), Pd(PPh₃)₄ (46 mg, 0.04 mmol) and1,3-dimethylbarbituric acid (97 mg, 1.1 mmol). The reaction mixture waspurified via silica gel chromatography using 5% MeOH in CH₂Cl₂ to obtainthe desired lactam as a white solid (10 mg, 0.02 mmol, 11% yield). ¹HNMR (400 MHz, DMSO-d6) δ 7.89-7.79 (m, 4H), 7.25 (d, J=4.6 Hz, 1H),7.00-6.97 (m, 2H), 6.82 (d, J=4.6 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.99(dd, J=9.0, 10.2 Hz, 1H), 3.89-3.79 (m, 2H), 3.19-3.12 (m, 2H), 2.70 (t,J=6.3 Hz, 2H), 2.42-2.36 (m, 1H), 2.11-2.05 (m, 1H), 1.91-1.77 (m, 2H).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=489.3;t_(R)=1.73 min.

Example 15 General Procedure 68

Under an N₂ atmosphere at −78° C., 2,2,2-trifluoroacetic anhydride (1equivalent) was added drop wise to a solution of the aniline (1equivalent), triethylamine (1 equivalent), and CH₂Cl₂ (0.6 M). Thereaction was allowed to warm to RT over a period of 30 minutes. Afterevaporating the solvents under reduced pressure, purification via silicagel chromatography using 7/3 hexanes/EtOAc gave desired product.

General Procedure 69

A mixture of acetamide (1 equivalent) and chlorosulfonic acid (5equivalent) was heated at 155° C. for 15 min. After cooling to RT, themixture was poured into ice water and extracted with EtOAc. The organiclayer was concentrated and purified via silica gel chromatography using7/3 hexanes/EtOAc gave desired product.

General Procedure 70

Under an N₂ atmosphere, a mixture of the sulfonyl chloride (1 mmol) andaminoheterocycle (1 mmol), and pyridine (1.0 mL) was stirred at RT for19 h. The crude product was purified via silica gel chromatography usingMeOH in CH₂Cl₂.

General Procedure 71

A solution of sulfonamide (1 equivalent), NaOH (10 equivalents), and H₂O(0.25 M) was stirred at RT for 1 h, then cooled to 0° C. Acetic acid (10equivalents) was added, and the reaction was stirred at 0° C. for 20min. The formed precipitate was filtered off and dried under vacuum togive the desired product.

General Procedure 72

To a solution of sulfathiazole (1-1.2 eq.) in CH₂Cl₂ (0.5 M) undernitrogen at RT was added a solution of trimethylaluminum in hexane(2.0M, 1-1.2 eq.) over 5 min. After stirring at RT for 20 min, asolution of the lactone (1 eq.) in CH₂Cl₂ (0.4 M) was added over 10 min.Stirring was continued for 18-36 h at RT or reflux, then the reactionmixture was cooled to 0° C. and quenched by careful addition of aqueous1M HCl. Phases were separated, and the aqueous phase was extracted withCH₂Cl₂ (2×). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via Gilson HPLC gave the desired product.

General Procedure 73

To a yellow solution of di-tert-butyl azo-dicarboxylate (2-4 eq.) in THF(0.4 M) at 0° C. under N₂ was slowly added tributylphosphine (2-4 eq.),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (1 eq.)in THF (0.3 M) at 0° C. under N₂. The reaction mixture was stirred for10 min. at this temperature, and quenched by addition of a saturatedaqueous NaHCO₃ solution. EtOAc was added, the phases were separated, andthe aqueous layer was extracted with EtOAc (2×). The combined organicextracts were dried over MgSO₄ and concentrated. Purification via GilsonHPLC gave the desired product.

2,2,2-Trifluoro-N-o-tolylacetamide

Synthesized according to general procedure 68. Under an N₂ atmosphere at−78° C., 2,2,2-trifluoroacetic anhydride (5.2 mL, 37.5 mmol) was addeddrop wise to a solution of o-toluidine (4.015 gm, 37.5 mmol),triethylamine (5.2 mL, 37.5 mmol), and CH₂Cl₂ (63 mL). The reaction wasallowed to warm to RT over a period of 30 minutes. After evaporating thesolvents under reduced pressure, purification via silica gelchromatography using 7/3 hexanes/EtOAc gave2,2,2-trifluoro-N-o-tolylacetamide (6.69 g, 85%). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=204.3; t_(R)=1.25 min.

3-Methyl-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride

Synthesized according to general procedure 69. A mixture of2,2,2-trifluoro-N-o-tolylacetamide (6.3 gm, 31 mmol) and chlorosulfonicacid (10.3 mL, 155 mmol) was heated at 155° C. for 15 min. After coolingto RT, the mixture was poured into ice water and extracted with EtOAc.The organic layer was concentrated and purified via silica gelchromatography using 0-25% EtOAc in hexanes gave3-methyl-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (7.8 g,85%). ¹H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.53 (d, J=1.3 Hz, 1H),7.46 (dd, J=8.1, 1.8 Hz, 1H), 7.21 (dd, J=8.1, 2.9 Hz, 1H), 2.18 (s,3H).

2,2,2-Trifluoro-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide

Synthesized according to general procedure 70. Under an N₂ atmosphere, amixture of 3-methyl-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonylchloride (7.5 g, 24.9 mmol) and 2-aminothiazole (2.49 g, 24.9 mmol), andpyridine (15 mL) was stirred at RT for 19 h. Purification via silica gelchromatography using 0-10% MeOH in CH₂Cl₂ gave2,2,2-trifluoro-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide(6.87 g, 76%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=366.1; t_(R)=1.13 min.

4-Amino-3-methyl-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 71. A solution of2,2,2-trifluoro-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide(1 g, 2.74 mmol), NaOH (1.09 g, 27.4 mmol), and H₂O (5 mL) was stirredat RT for 1 h, then cooled to 0° C. 1 N hydrochloric acid (27.4 mL, 27.4mmol) was added, and the reaction was stirred at 0° C. for 20 min. Theformed precipitate was filtered off and dried under vacuum to give4-amino-3-methyl-N-(thiazol-2-yl)benzenesulfonamide (232 mg, 31%).

(S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl-4-hydroxy-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)butamide

Synthesized according to general procedure 72. To a solution of4-amino-3-methyl-N-(thiazol-2-yl)benzenesulfonamide (25 mg, 0.093 mmol)in CH₂Cl₂ (0.25 mL) under nitrogen at RT was added a solution oftrimethylaluminum in hexane (2.0M, 0.046 mL, 0.093 mmol) over 5 min.After stirring at RT for 20 min, a solution of the(S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-dihydrofuran-2(3H)-one (78mg, 0.278 mmol) in CH₂Cl₂ (0.25 mL) was added over 10 min. Stirring wascontinued for 18-36 h at RT or reflux, then the reaction mixture wascooled to 0° C. and quenched by careful addition of aqueous 1M HCl.Phases were separated, and the aqueous phase was extracted with CH₂Cl₂(2×). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via silica gel chromatography using 2-10%MeOH in CH₂Cl₂ gave the(S)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl-4-hydroxy-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)butamide(5 mg, 10%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=521.3; t_(R)=1.53 min.

(S)-4-(3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-3-methyl-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 73. To a yellow solution ofdi-tert-butyl azo-dicarboxylate (81 mg, 0.35 mmol) in THF (0.2 mL) at 0°C. under N₂ was slowly added tributylphosphine (0.087 mL, 0.35 mmol),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (46 mg,0.088 mmol) in THF (0.25 mL) at 0° C. under N₂. The reaction mixture wasstirred for 10 min. at this temperature, and quenched by addition of asaturated aqueous NaHCO₃ solution. EtOAc was added, the phases wereseparated, and the aqueous layer was extracted with EtOAc (2×2 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated. LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=503.1;t_(R)=1.72 min.

2,2,2-Trifluoro-N-(2-fluorophenyl)acetamide

Synthesized according to general procedure 68. Under an N₂ atmosphere at−78° C., 2,2,2-trifluoroacetic anhydride (5.2 mL, 37.5 mmol) was addeddrop wise to a solution of 2-fluoroaniline (4.16 gm, 37.5 mmol),triethylamine (5.2 mL, 37.5 mmol), and CH₂Cl₂ (63 mL). The reaction wasallowed to warm to RT over a period of 30 minutes. After evaporating thesolvents under reduced pressure, purification via silica gelchromatography using 7/3 hexanes/EtOAc gave2,2,2-trifluoro-N-(2-fluorophenyl)acetamide as a white solid (6.69 g,88%). ¹H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 7.64-7.25 (m, 4H). LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=208;t_(R)=1.18 min.

3-Fluoro-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride

Synthesized according to general procedure 69. A mixture of2,2,2-trifluoro-N-o-tolylacetamide (5.6 gm, 27.05 mmol) andchlorosulfonic acid (9 mL, 135 mmol) was heated at 155° C. for 15 min.After cooling to RT, the mixture was poured into ice water and extractedwith EtOAc. The organic layer was concentrated and purified via silicagel chromatography using 0-25% EtOAc in hexanes gave3-fluoro-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (5.13g, 62%). ¹H NMR (400 MHz, DMSO-d6) δ 11.4 (s, 1H), 7.53 (d, J=1.3 Hz,1H), 7.46 (dd, J=8.1, 1.8 Hz, 1H), 7.21 (dd, J=8.1, 2.9 Hz, 1H).

2,2,2-Trifluoro-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide

Synthesized according to general procedure 70. Under an N₂ atmosphere, amixture of the 3-fluoro-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonylchloride (5.0 g, 16.4 mmol) and 2-aminothiazole (1.64 g, 16.4 mmol), andpyridine (9.6 mL) was stirred at RT for 19 h. Purification via silicagel chromatography using 0-10% MeOH in CH₂Cl₂ gave2,2,2-trifluoro-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide(3.28 g, 54%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=370.1; t_(R)=1.07 min.

4-Amino-3-methyl-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 71. A solution of2,2,2-trifluoro-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide(2.0 g, 5.42 mmol), NaOH (2.17 g, 54.2 mmol), and H₂O (9.7 mL) wasstirred at RT for 1 h, then cooled to 0° C. 1 N hydrochloric acid (54.2mL, 54.2 mmol) was added, and the reaction was stirred at 0° C. for 20min. The formed precipitate was filtered off and dried under vacuum togive 4-amino-3-fluoro-N-(thiazol-2-yl)benzenesulfonamide (1.03 g, 70%).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=274.1;t_(R)=0.51 min

(S)-2-(6-Chloro-3,4-dihyroquinolin-1(2H)-yl-4-hydroxy-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)butamide

Synthesized according to general procedure 72. To a solution of4-amino-3-fluoro-N-(thiazol-2-yl)benzenesulfonamide (0.5 g, 1.83 mmol)in CH₂Cl₂ (4.3 mL) under nitrogen at RT was added a solution oftrimethylaluminum in hexane (2.0M, 0.91 mL, 1.83 mmol) over 5 min. Afterstirring at RT for 20 min, a solution of the(S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-dihydrofuran-2(3H)-one(0.46 g, 1.83 mmol) in CH₂Cl₂ (4.3 mL) was added over 10 min. Stirringwas continued for 18-36 h at RT or reflux, then the reaction mixture wascooled to 0° C. and quenched by careful addition of aqueous 1M HCl.Phases were separated, and the aqueous phase was extracted with CH₂Cl₂(2×10 mL). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via silica gel chromatography using 2-10%MeOH in CH₂Cl₂ gave the(S)-2-(6-chloro-3,4-dihyroquinolin-1(2H)-yl-4-hydroxy-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)butamide(391 mg, 41%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=525.1; t_(R)=1.56 min.

(S)-4-(3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-3-fluoro-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to general procedure 73. To a yellow solution ofdi-tert-butyl azo-dicarboxylate (138 mg, 0.6 mmol) in THF (0.75 mL) at0° C. under N₂ was slowly added tributylphosphine (0.15 mL, 0.6 mmol),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (80 mg,0.15 mmol) in THF (0.25 mL) at 0° C. under N₂. The reaction mixture wasstirred for 10 min. at this temperature, and quenched by addition of asaturated aqueous NaHCO₃ solution. EtOAc was added, the phases wereseparated, and the aqueous layer was extracted with EtOAc (2×2 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated. LC/MS(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=507.1;t_(R)=1.77 min.

Example 16 General Procedure 74

A mixture of bromide (1.0 equivalent, 1.0 mmol), pyrrolidine (1.0equivalent, 1.0 mmol), Pd₂(dba)₃ (0.03 equivalents, 0.03 mmol),biphenyl-2-yldi-tert-butylphosphine (0.12 equivalents, 0.12 mmol),sodium tert-butoxide (2.8 equivalents, 2.8 mmol), and toluene (2.6 mL)was heated under N₂, at 70° C. for 1 hr. The reaction was cooled to RTand then neutralized to pH=7 with 1.0 N HCl aqueous solution. The crudesolid was purified via silica gel chromatography using MeOH in CH₂Cl₂ togive the desired products.

(R)-tert-butyl1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)pyrrolidin-3-ylcarbamate

Prepared using general procedure 74. The reaction was set up with4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (750 mg, 2.34 mmol),(R)-tert-butyl pyrrolidin-3-ylcarbamate (436 mg, 2.34 mmol), Pd₂(dba)₃(64 mg, 0.07 mmol), biphenyl-2-yldi-tert-butylphosphine (84 mg, 0.28mmol), sodium tert-butoxide (630 mg, 6.6 mmol), and toluene (6.0 mL).Purification via silica gel chromatography using 10% MeOH in CH₂Cl₂ gavethe desired pyrrolidine as an orange solid (213 mg, 0.49 mmol, 21%yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1obs=326.3; t_(R)=1.39 min.

General Procedure 75

tert-Butyl pyrrolidin-3-ylcarbamate (1 equivalent, 1 mmol) was added to4.0 N HCl in dioxane (43 equivalents, 43 mmol). The reaction was stirredat 25° C. for 5 minutes. The obtained precipitate was filtered off anddissolved in MeOH (10 mL). The organic solution was dried (MgSO₄) andevaporated to dryness to give the desired pyrrolidineamine.

(S)-4-(3-aminopyrrolidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamidehydrochloride

Prepared using general procedure 75. The reaction was set up with(S)-tert-butyl1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)pyrrolidin-3-ylcarbamate(995 mg, 2.34 mmol) and 4.0 N HCl in dioxane (25 mL, 100 mmol) toisolate the desired pyrrolidineamine as an orange solid (229 mg, 0.63mmol, 27% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=; t_(R)=min

General Procedure 76

A solution of acid (1.1 equivalents, 1.1 mmol), HATU reagent (1.1equivalent, 1.1 mmol), DMF (2.5 mL), and CH₂Cl₂ (2.5 mL) was stirredunder N₂, at 0° C. for 30 minutes. To this solution was added theaminopyrrolidine (1 equivalent, 1 mmol) and diisopropylethylamine (2.2equivalent, 2.2 mmol). The reaction was stirred at 25° C. for 19 hours.The obtained solution was purified via Gilson HPLC to give the desiredpyrrolidinesulfonamide.

(S)—N-(1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)pyrrolidin-3-yl)-2-(6-chloro-1H-indol-1-yl)acetamide

Prepared using general procedure 76. The reaction was set up with2-(6-chloro-1H-indol-1-yl)acetic acid (32 mg, 0.10 mmol), HATU reagent(38 mg, 0.10 mmol), DMF (0.25 mL), and CH₂Cl₂ (0.25 mL),(S)-4-(3-aminopyrrolidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamidehydrochloride (30 mg, 0.09 mmol) and diisopropylethylamine (35 mg, 0.20mmol). The desired aminopyrrolidine was obtained as a white solid (14mg, 0.03 mmol, 30% yield). ¹H NMR (400 MHz, DMSO-d6) δ 8.78-8.77 (m,1H), 8.62 (d, J=6.7 Hz, 1H), 8.55 (d, J=7.0 Hz, 1H), 8.40 (s, 1H),7.65-7.51 (m, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.35 (d, J=3.2 Hz, 1H), 7.03(dd, J=1.9, 8.4 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H), 6.48 (s, 1H), 6.46 (dd,J=0.8, 3.2 Hz, 1H), 4.82 (s, 2H), 4.40 (d, J=5.9 Hz, 1H), 3.63-3.40 (m,5H), 2.34-2.28 (m, 1H), 1.99-1.91 (m, 1H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=517.3; t_(R)=2.95 min.

(R)—N—((R)-1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)pyrrolidin-3-yl)-2-(4-fluoro-1H-indol-1-yl)propanamide

Prepared using general procedure 76. The reaction was set up with(R)-2-(4-fluoro-1H-indol-1-yl)propanoic acid (27 mg, 0.10 mmol), HATUreagent (38 mg, 0.10 mmol), DMF (0.25 mL), and CH₂Cl₂ (0.25 mL),(R)-4-(3-aminopyrrolidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamidehydrochloride (30 mg, 0.09 mmol) and diisopropylethylamine (35 mg, 0.20mmol). The desired aminopyrrolidine was obtained as a white solid (33mg, 0.06 mmol, 72% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=515.5; t_(R)=2.94 min.

(S)—N-(1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)pyrrolidin-3-yl)-2-(6-chloro-1H-indol-1-yl)acetamide

Prepared using general procedure 76. The reaction was set up with2-(6-chloro-1H-indol-1-yl)acetic acid (20 mg, 0.10 mmol), HATU reagent(38 mg, 0.10 mmol), DMF (0.25 mL), and CH₂Cl₂ (0.25 mL),(R)-4-(3-aminopyrrolidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamidehydrochloride (30 mg, 0.09 mmol) and diisopropylethylamine (35 mg, 0.20mmol). The desired aminopyrrolidine was obtained as a white solid (33mg, 0.06 mmol, 72% yield). ¹H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H),8.61 (d, J=6.7 Hz, 1H), 7.57 (dd, J=18.0, 8.6 Hz, 3H), 7.48 (s, 1H),7.35 (d, J=3.2 Hz, 1H), 7.20 (d, J=4.6 Hz, 1H), 7.03 (dd, J=8.4, 1.8 Hz,1H), 6.75 (d, J=4.6 Hz, 1H), 6.59 (d, J=8.9 Hz, 2H), 6.46 (d, J=3.2 Hz,1H), 4.82 (s, 2H), 4.40 (d, J=5.3 Hz, 1H), 3.56-3.52 (m, 1H), 3.48-3.36(m, 1H), 3.35-3.29 (m, 1H), 3.18 (dd, J=10.1, 3.4 Hz, 1H), 2.25-2.16 (m,1H), 1.98-1.92 (m, 1H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=516.5; t_(R)=3.09 min.

Table 3 below recites the analytical data for the compounds of Table 2above.

Cmpd LC/MS LC/RT No. M + 1 min 1 530.1 3.18 2 447 1.46 3 544 3.28 4 4782.55 5 558 3.4 6 527.3 2.78 7 547.3 3.19 8 489 1.72 9 493.3 2.65 10484.2 3.24 11 494.3 2.71 12 461 0.99 13 552.3 2.68 14 525.3 2.84 15511.2 3.15 16 492 2.95 17 466.3 1.44 18 503 1.06 19 510 2.98 20 430 1.5821 439.5 2.49 22 517 2.84 23 411 0.37 24 526 2.84 25 472.2 1.88 26 501.33.08 27 542.4 2.76 28 493.3 2.79 29 513.5 1.59 30 487.3 1.94 31 527 3.2732 515.2 2.96 33 528 3.17 34 488 2.15 35 555.1 2.84 36 473.3 2.44 37525.3 3 38 504.3 1.82 39 546.3 2.85 40 491.3 2.5 41 457 1.09 42 512.23.08 43 463 2.05 44 489.3 1.73 45 528 2.87 46 535.5 2.64 47 554.3 2.6848 557 2.94 49 499.6 2.88 50 530.1 1.01 51 443 0.98 52 508.5 2.95 53544.2 3.02 54 576.3 3.11 55 551.2 2.91 56 512.5 2.55 57 593 2.83 58 5473.19 59 528.3 0.98 60 544 3.01 61 485.2 2.31 62 410.2 1.61 63 529 2.7364 476 2.12 65 503 1.76 66 535 2.97 67 467 1.85 68 545.3 1.82 69 555.52.91 70 518 1.81 71 535.3 2.59 72 531 2.8 73 493 1.69 74 463.2 2.59 75434 1.47 76 523.2 3.04 77 494.5 2.83 78 450 1.57 79 530.2 3.11 80 480.11.58 81 523.3 2.85 82 503 1.71 83 539.5 2.48 84 544 2.9 85 441.2 1.99 86525.2 3.03 87 489.2 1.36 88 555 1.1 89 478 2.6 90 493 1.96 91 435.2 1.4992 559.3 3.1 93 528 3.16 94 544 3.29 95 455.5 1.59 96 532.2 3.11 97544.3 2.4 98 524.2 2.95 99 495.5 2.59 100 483.2 2.9 101 490.2 2.81 102515.05 1.63 103 578.3 3.12 104 446.3 1.43 105 455.3 1.58 106 480.3 1.5107 484.5 1.96 108 484.5 3.11 109 577.3 2.91 110 486 2.51 111 544.5 2.91112 535.5 2.8 113 502 3.8 114 502.3 1.87 115 475 3.6 116 484 1.63 117530.2 3.1 118 589.5 3.33 119 484 1.66 120 534.8 2.94 121 527.2 1.63 122473 0.99 123 526 3.08 124 532.3 3.09 125 592.4 3.04 126 528 3.15 127 4951.76 128 505 1.54 129 564.5 3.28 130 544.3 2.91 131 558.3 3.4 132 381.30.41 133 502.3 1.08 134 472 2.08 135 447 0.92 136 415.2 2.33 137 5262.78 138 421.1 2.68 139 521.5 2.84 140 547 3.09 141 460 1.66 142 508.31.05 143 545.5 3.08 144 463 1.01 145 470.3 2.43 146 516.5 2.18 147 5082.58 148 555.1 2.85 149 514.4 2.74 150 518.3 1.92 151 530.2 2.91 152525.3 2.89 153 531.3 3.01 154 576.3 3.21 155 525.3 2.95 156 468 1.65 157443 1 158 555.3 2.85 159 510.4 3.08 160 527 1.64 161 511.2 2.71 162367.3 0.34 163 447 1.5 164 505.3 2.88 165 548.3 1.05 166 458 1.75 167444.4 1.57 168 528 2.85 169 528.2 3.06 170 558.3 3.14 171 484 1.71 172526 2.67 173 544 3.3 174 531 3.25 175 496 2.66 176 560.3 3.39 177 541.23.12 178 459.4 2.96 179 488.5 2.16 180 570.3 2.8 181 452 1.54 182 4711.19 183 487.3 1.93 184 545 2.9 185 575.5 3.31 186 497.3 2.93 187 5352.94 188 548.3 1.36 189 521.4 2.58 190 523.5 2.92 191 458.4 1.78 192 5521.92 193 530 2.9 194 530 2.9 195 469 1.7 196 492.4 2.53 197 450.2 2.05198 464 1.69 199 561 3.01 200 516.3 2.7 201 496 2.26 202 464 1.74 203517 2.95 204 524.4 1.13 205 542 3.22 206 588 3.37 207 455.3 2.98 208608.4 3.47 209 508 3.16 210 501 2.64 211 516.5 1.57 212 434 1.48 213518.1 1.77 214 444 1.71 215 484 1.72 216 516.3 2.76 217 506 2.89 218493.2 1.55 219 489 1.72 220 466.3 2.51 221 505.3 2.55 222 443.5 1 223574 2.9 224 515.3 3.1 225 545 3.33 226 564.5 3.26 227 526.3 2.89 228 5553.22 229 513.5 1.62 230 509.5 1.79 231 507 1.77 232 496.2 3.16 233 475.23.21 234 491.3 2.42 235 528.2 2.85 236 514 2.73 237 499 2.79 238 514.23.23 239 509 2.62 240 529 3.18 241 444.4 1.58 242 497.2 2.97 243 5142.76 244 500.3 1.74 245 576.5 3.18 246 575.2 3.45 247 530 3.17 248 468.32.31 249 525.2 3.23 250 536.5 2.63 251 531 2.94 252 514.1 2.83 253 536.32.68 254 536.5 1.25 255 529 2.72 256 490 2.08 257 544 2.83 258 509.52.87 259 531 3.25 260 490.3 2.4 261 441.2 2.92 262 531 2.81 263 444 1.7264 512.3 3.03 265 495 1.06 266 547.2 3.38 267 480.2 1.54 268 528 3.15269 575.5 3.05 270 546.3 2.91 271 497.5 3.09 272 533.3 1.29 273 609.33.32 274 545 3.3 275 530.2 3.28 276 490.3 2.13 277 540 2.72 278 544.32.78 279 458.2 1.31 280 509.5 2.87 281 536.3 2.73 282 460.3 1.4 283 5122.12 284 552.3 1.33 285 472 1.63 286 495.5 1.57 287 421.3 0.88 288 521.42.62 289 493.3 1.63 290 471.3 1.37 291 463 0.96 292 544 3.15 293 455.51.53 294 514 3.09 295 566.5 2.92 296 510 2.81 297 592.3 3.35 298 546.43.22 299 527.2 1.62 300 571.5 3.18 301 533.3 3.28 302 493.2 1.46 303 5283.16 304 497 2.86 305 526.3 2.93 306 526.3 2.94 307 441.4 2.98 308 429.41.87 309 449.3 1.51 310 560.3 3.04 311 474 2.34 312 571.5 3.5 313 574.13.46 314 517 2.54 315 547.2 3.38 316 558.3 3.1 317 484 1.73 318 551.52.59 319 458 2.52 320 486 2.41 321 542 2.91 322 486.3 2.58 323 477.22.31 324 493.3 1.98 325 510.2 3.08 326 500 2.74 327 476.2 1.46 328 455.31.61 329 564 3.17 330 463 1.03 331 509 2.62 332 546 3.3 333 525.3 2.72334 483 0.29 335 493 1.65 336 497 3.04 337 515.3 3.1 338 514.5 3.03 339429.5 2.03 340 558.3 2.9 341 544 3.26 342 514.3 2.81 343 490.3 1.77 344536.3 2.7 345 520.5 1.15 346 480 2.67 347 503 1.06 348 457.5 1.13 349505.3 2.89 350 450.5 1.53 351 482.5 1.05 352 557.3 2.11 353 545 3.27 354531.3 3.24 355 450.3 1.64 356 514.5 3.03 357 484 2.9 358 457.2 2.5 359459.5 2.37 360 464.3 2.48 361 475 1.71 362 560.3 3.12 363 477.5 2.24 364493 1.86 365 484 1.77 366 518 3.2 367 444.4 1.64 368 455.3 1.59 369 4891.08 370 516.4 3.02 371 505.3 2.68 372 502 1.76 373 472 1.96 374 434 1.5375 429 0.89 376 560.5 2.99 377 516.3 2.41 378 497.97 2.72 379 529.9 3.1380 498.3 2.01 381 530.3 1.55 382 461.2 2.74 383 593.3 3.32 384 540.32.67 385 541.5 2.99 386 440.3 1.9 387 588 3.37 388 459.2 1.35 389 4461.4 390 542.5 3.02 391 511.2 2.94 392 501 2.81 393 541.2 3.07 394 4962.76 395 444.4 1.59 396 564 3.27 397 514 2.78 398 560 2.98 399 473 1.03400 514.5 3.02 401 552.3 1.37 402 473 2.67 403 524.2 3.16 404 515.3 3.1405 530 3.27 406 531 2.9 407 505.3 2.92 408 524.5 2.74 409 579.3 2.74410 495.2 2.16 411 544.3 2.85 412 514.5 1.08 413 472.3 2.29 414 532.32.98 415 511.5 1.24 416 507.3 2.81 417 550.3 2.73 418 515.3 3.06 419514.2 2.7 420 546.2 3.2 421 473.2 3.15 422 519.5 3 423 454.2 2.58 424555.3 3.18 425 525.2 2.87 426 556 2.83 427 540.2 3.06 428 511 2.9 429473 1.46 430 539.5 2.89 431 531.3 3.24 432 487 1.61 433 494.5 2.51 434493.3 2.38 435 461.5 0.99 436 529 2.9 437 497 2.8 438 544.2 2.98 439528.3 3.09313 440 528.1 2.85 441 473.1 3.41 442 482.5 2.55 443 469 1.59444 561.1 2.8 445 511 2.85 446 546.3 3.09 447 475.1 2.43 448 457.5 1.57449 473.3 1.67 450 468.1 2.01 451 516.2 3.23 452 477 1.14 453 560.5 2.94454 532.2 2.82 455 489.2 1.32 456 444.4 1.57 457 468.3 2.13 458 531.33.09 459 531 2.94 460 624 1.99 461 537 2.76 462 509.2 3.06 463 472 3.7464 514.5 3.07 465 515.5 1.68 466 600.3 3.24 467 441.3 2.67 468 512.22.97 469 507.3 2.18 470 517.4 2.31 471 447 1.41 472 495.3 2.58 473 529.93.09 474 545.5 3.1 475 481 1.01 476 511 1.12 477 514 3.08 478 459.2 3.06479 472 2.45 480 457.5 1.6 481 543.3 2.85 482 489.3 3.27 483 452.3 2.36484 516.2 2.79 485 512.3 0.97 486 504.3 2.83 487 482.3 2.38 488 609.33.3 489 511 2.9 490 490.3 3.47 491 511 2.84 492 475 3.55 493 490.3 2.85494 546.5 2.82 495 668.5 3.99 496 511.5 1.21 497 510.4 2.46 498 510.51.58 499 556 3.14 500 488 2.44 501 469.5 1.69 502 539.5 2.88 503 398.22.09 504 461.2 2.03 505 469.5 1.7 506 472.2 1.88 507 455.3 2.09 508514.5 3.05 509 453 3.11 510 528.1 2.74 511 535.2 2.97 512 482 2.29 513535 2.94 514 484 1.62 515 516.5 2.23 516 544.5 3.27 517 471.3 2.65 518530.5 1 519 509.4 3.31 520 482.3 0.99 521 444.4 1.52 522 514.5 3.03 523489.3 3.36 524 498 2.97 525 372.1 3.03 526 531.3 3.05 527 524.2 2.85 528561.3 3.44 529 528.2 3.15 530 506 1.56 531 544.3 2.88 532 593.5 3.22 533472.2 1.86 534 489 1.78 535 480.3 2.66 536 379.3 0.39 537 530 3.27 538525.3 2.8 539 559.3 3.19 540 465 0.97 541 603.3 3 542 511.5 1.29 543 4611.03 544 455.3 1.53 545 525.3 3.01 546 450.3 1.58 547 615.3 3.64 548518.3 1.19 549 574 3.23 550 510 3.1 551 580.3 3.12 552 458.4 1.78 553489 1.74 554 531.3 3.07 555 430 1.53 556 540.2 3.01 557 530 2.96 558493.3 1.64 559 514.2 3.23 560 529 2.9 561 450.3 1.63 562 515 2.94 563546.3 2.95 564 492.2 1.96 565 472 2.65 566 472 1.91 567 516.4 2.92 568502 2.55 569 514.2 2.98 570 459.5 1.53 571 455 1.6 572 539.5 3.08 573564.5 3.28 574 508 1.33 575 531.2 3.21 576 510.3 2.76 577 578.2 2.83 578558.3 1.95 579 519.2 1.72 580 461 1.03 581 501.3 1.13 582 494.5 0.8 583455.3 2.79 584 528.3 1.03 585 529 2.74 586 475 1.69 587 538.5 1.98 588531 2.94 589 510.4 3.07 590 571.3 2.96 591 490.3 1.72 592 558.3 2.11 593442.3 0.74 594 536.5 1.04 595 509.5 2.84 596 525 2.77 597 574.3 3.21 598555 3.24 599 543.3 1.83 600 508.5 2.95 601 579.3 2.82 602 525.3 2.99 603570 2.61 604 527.2 2.96 605 463.3 1.98 606 571.3 3 607 535.2 2.98 608515.5 3.14 609 475 1.43 610 514.5 3.05 611 501 2.74 612 500 2.73 613506.2 2.96 614 542 2.83 615 544.3 2.76 616 516 2.63 617 503.2 2.68 618489 1.72 619 599.5 3.32 620 484.5 1.03 621 509.2 2.86 622 528.3 3.13 623528 3.15 624 525.2 2.9 625 519.5 2.99 626 530.2 3.04 627 468 2.26203 628488 2.09 629 558 3.02 630 472 1.85 631 562.3 2.99 632 503 3.29 633 536.31.21 634 514 3.08 635 551 0.54 636 502.3 1.11 637 460 1.53 638 552.3 2.7639 545.5 3.26 640 497.5 3.08 641 489 1.74 642 545 2.9 643 512 1.25 644441.2 1.25 645 441.3 1.43 646 530.3 2.94 647 442.3 3.06 648 491 3 649541.1 3.11 650 556 3.14 651 511.4 3.13 652 484.3 1.71 653 578.5 3.11 654531.1 3.27 655 521.5 2.73 656 518.3 1.21 657 530.2 3.15 658 561 3.19 659530.2 3.16 660 443 1.01 661 496.3 2.78 662 529 3.15 663 509.4 2.84 664508.5 2.91 665 500.3 1.73 666 526 2.68 667 511.5 1.74 668 498.5 1.16 669545.5 3.11 670 531.3 1.19 671 521.4 2.62 672 477.2 1.43 673 518.3 1.21674 511 1.13 675 531.3 3.24 676 505.3 2.92 677 569 1.97 678 471.3 1.45679 508.5 2.8 680 542.2 3.22 681 419 2.82 682 513.3 1.98 683 439.5 2.32863 525.3 2.98 685 448 1.61 686 515 2.89 687 559.1 3.08 688 560 3.31 689578.3 2.73 690 458 1.81 691 552.5 1.27 692 489.5 2.79 693 510.2 3.09 694544.3 2.81 695 522.3 2.61 696 492.3 1.68 697 457 1.07 698 547.5 3.41 699529 3.21 700 544 3.32 701 516.3 3.17 702 558.4 2.94 703 544.9 3.3 704554 3.17 705 447 0.93 706 419.3 2.95 707 459.3 1.35 708 535.3 1.62 709529 2.84 710 443 1.07 711 524.5 2.66 712 540.3 3.01 713 452 1.49 714 4771.13 715 426.1 3.08 716 495 2.29 717 511 2.98 718 530.3 2.98 719 464.31.68 720 498.3 1.08 721 528.1 2.84 722 528 3.15 723 485.2 2.61 724 4290.88 725 450.3 2.33 726 545 3.29 727 544 3.08 728 510.5 2.75 729 614.33.54 730 515.5 3.18 731 461 1.02 732 547 3.12 733 529 3.21 734 535.22.88 735 528 3.15 736 457 1.1 737 522.3 2.66 738 545 3.25 739 508.4 2.78740 531.1 3.15 741 544 3.27 742 541.5 2.96 743 521.5 2.74 744 521.3 2.9745 554.9 3.03 746 510.5 2.99 747 471.3 2.43 748 478.3 2.06 749 510.52.9 750 476.3 3.06 751 499.3 3.11 752 401.3 2.71 753 552.3 1.3 754 608.43.52 755 662 1.86 756 555.3 2.49 757 529 2.84 758 538.5 1.04 759 5272.86 760 539.5 2.88 761 500.3 2.39 762 561.3 3.09 763 493.2 1.55 764 5293.17 765 477.3 2.46 766 477 1.08 767 490.3 2.35 768 477 1.04 769 5283.15 770 475.3 1.64 771 510.5 3.05 772 555.3 2.57 773 528.2 3.13 774 5253 775 477 1.12 776 444.4 1.68 777 509.5 2.87 778 539.5 2.42 779 546 2.94780 459.3 1.57 781 554 3.37 782 516 3.9 783 544 2.9 784 475.2 3.19 785447 0.92 786 525.1 2.81 787 493 2.78 788 530.3 2.98 789 481.1 2.88 790525 2.92 791 441.4 1.25 792 504.5 1.83 793 490 2.27 794 500.59 2.83 795539.3 2.93 796 511.4 2.89 797 515.3 3.09 798 495.5 1.57 799 519.5 3 800546 3.37 801 482 2.73 802 521.3 2.87 803 589.3 3.32 804 542.4 2.8 805564.3 3.2 806 502 2.65 807 565 2.91 808 496.2 3.16 809 529.3 1.59 810623.2 3.47 811 515.3 3.1 812 496 2.69 813 558.3 3.1 814 507 1.73 815493.3 2.28 816 519 2.77 817 528 3.14 818 528.1 2.96 819 460 1.56 820440.2 1.85 821 535.3 2.63 822 538.3 2.66 823 545.5 3.11 824 497.2 2.04825 511.3 2.95 826 455 1.32 827 517 2.83 828 524.5 2.81 829 533.2 2.81830 516.2 3.28 831 536.5 1.01 832 479.3 2.62 833 553 1.29 834 545 3.33835 466.3 2.41 836 501 2.78 837 602 3.5 838 498.1 3.04 839 515.3 3.1 840459.3 2.02 841 516.3 2.7 842 551.2 2.97 843 469 3.07 844 538 2.96 845483 1.7 846 509.2 2.16 847 536.3 2.71 848 560.3 2.94 849 490.3 2.41 850596.5 3.26 851 536.5 2.66 852 560.3 3.09 853 452 1.65 854 471.2 2.45 855528 3.05 856 531 3.21 857 560.3 3.1 858 516 2.82 859 529.3 1.68 860 5531.29 861 512.3 0.97 862 530.5 1 863 524.4 1.13 864 508.5 1.03 865 5221.83 866 528.3 0.98 867 508 1.75 868 530.1 1.01 869 562 2.03 870 5621.92 871 379.3 0.39 872 528 1.1 873 507.2 1.71 874 518 1.89 875 488 1.52876 494 1.73 877 367.3 0.34 878 528.3 1.03 879 525.3 0.99 880 520.3 1.15881 548.3 1.17 882 381.3 0.41 883 507 1.75 884 548.3 1.05 885 536.5 1.01886 520.3 1.11 887 508.3 1.05 888 508 1.33 889 520.3 1.12 890 566.3 1.41891 569 1.97 892 457.5 1.13 893 520.1 1.16 894 508 1.77 895 533.3 1.29896 507 1.8 897 517.3 1.28 898 536.3 1.22 899 536.5 1.04 900 488 1.68901 536.3 1.22 902 494 1.68 903 488 1.6

Assays for Detecting and Measuring NaV Inhibition Properties of Compound

Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (See,Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69(4): 1272-80, andGonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4(4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See,Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today4(9): 431-439).

VIPR® Optical Membrane Potential Assay Method with Chemical Stimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

-   1) On the day of the assay, medium is aspirated and cells are washed    twice with 225 μL of Bath Solution #2 (BS#2).-   2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin    stock solution with 10% Pluronic 127 1:1 and then dissolving the mix    in the appropriate volume of BS#2.-   3) After bath solution is removed from the 96-well plates, the cells    are loaded with 80 L of the CC2-DMPE solution. Plates are incubated    in the dark for 30 minutes at room temperature.-   4) While the cells are being stained with coumarin, a 15 μL oxonol    solution in BS#2 is prepared. In addition to DiSBAC₂(3), this    solution should contain 0.75 mM ABSC1 and 30 μL veratridine    (prepared from 10 mM EtOH stock, Sigma #V-5754).-   5) After 30 minutes, CC2-DMPE is removed and the cells are washed    twice with 225 L of BS#2. As before, the residual volume should be    40 μL.-   6) Upon removing the bath, the cells are loaded with 80 μL of the    DiSBAC₂(3) solution, after which test compound, dissolved in DMSO,    is added to achieve the desired test concentration to each well from    the drug addition plate and mixed thoroughly. The volume in the well    should be roughly 121 μL. The cells are then incubated for 20-30    minutes.-   7) Once the incubation is complete, the cells are ready to be    assayed on VIPR® with a sodium add back protocol. 120 μL of Bath    solution #1 is added to stimulate the NaV dependent depolarization.    200 μL tetracaine was used as an antagonist positive control for    block of the NaV channel.    Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{11mu} n\; m} - {background}_{460\mspace{11mu} n\; m}} \right)}{\left( {{intensity}_{580\mspace{11mu} n\; m} - {background}_{580\mspace{11mu} n\; m}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i); is thencalculated. For the Na⁺ addback analysis time windows, baseline is 2-7sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compoundSolutions [mM]

Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH 7.4with NaOH

Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4 withKOH (final K concentration˜5 mM)

CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at −20°C.

DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.

ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at roomtemperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV1.3 inhibition activity ismeasured using the optical membrane potential method #2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂O

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading Protocol

2×CC2-DMPE=20 μM CC2-DMPE:

10 mM CC2-DMPE is vortexed with an equivalent volume of 10% pluronic,followed by vortexing in required amount of HBSS containing 10 mM HEPES.Each cell plate will require 5 mL of 2×CC2-DMPE. 50 μL of 2×CC2-DMPE isto wells containing washed cells, resulting in a 10 μM final stainingconcentration. The cells are stained for 30 minutes in the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1:

The required amount of 10 mM DISBAC₂(3) is added to a 50 ml conical tubeand mixed with 1 μL 10% pluronic for each mL of solution to be made andvortexed together. Then HBSS/HEPES is added to make up 2× solution.Finally, the ABSC1 is added.

The 2×DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the2×DiSBAC₂(3) w/ABSCl. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

Assay buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose, pH 7.40, 330 mOsm

Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO

Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO

Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO

ABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

Insert or use electrodes into each well to be assayed.

Use the current-controlled amplifier to deliver stimulation wave pulsesfor 3 s. Two seconds of pre-stimulus recording are performed to obtainthe un-stimulated intensities. Five seconds of post-stimulationrecording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{11mu} n\; m} - {background}_{460\mspace{11mu} n\; m}} \right)}{\left( {{intensity}_{580\mspace{11mu} n\; m} - {background}_{580\mspace{11mu} n\; m}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 M using an Axopatch 200B amplifier (AxonInstruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl2 (1), EGTA(1.5), CaCl2 (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH2PO4 (0.44), MgCl2 (0.5), MgSO4 (0.41), NaHCO3 (4), Na2HPO4 (0.3),glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

Current-Clamp Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp700 A amplifier (Axon Inst). Borosilicate pipettes (4-5 Mohm) werefilled with (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2MgCl₂, (buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140NaCl, 3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

The exemplified compounds of Table 2 herein are active against one ormore sodium channels as measured using the assays described hereinabove.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

The invention claimed is:
 1. A method of treating or lessening theseverity in a subject of acute, chronic, neuropathic, or inflammatorypain, epilepsy visceral pain, osteoarthritis pain, radicular pain, backpain, head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain, comprisingadministering an effective amount of a compound according to formula I,

or a pharmaceutically acceptable salt thereof; wherein: ring Z is a 5-6membered unsaturated or aromatic ring having 1-4 ring heteroatomsselected from O, S, or N, wherein Z is optionally substituted with up toq occurrences of R^(Z) substitutents, wherein each R^(Z) isindependently selected from R¹, R², R³, R⁴, or R⁵; and q is 0-4; W andY₁ each is independently CH or N, provided that at least one of W and Y₁is N; x and y each is 2; w is 0-4; v is 0 or 1; z is 0-4; V and X eachis a bond, 0, NR², or C(R²)₂; Q is a bond or a C1-C6 straight orbranched alkylidene chain, wherein up to two non-adjacent methyleneunits of Q are optionally and independently replaced by —CO—, —CS—,—COCO—, —CONR²—, —CONR²NR²—, —CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—,—OCONR²—, —NR²NR², —NR²NR²CO—, —NR²CO—, —S—, —SO, —SO₂—, —NR²—,—SO₂NR²—, NR²SO₂—, —NR²SO₂NR²—, or a spirocycloalkylene moiety; R^(Q) isa 3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected from O, S,N, or NH, or an 8-15 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring or tricyclic fused or spirocyclic ring systemhaving 0-5 heteroatoms independently selected from O, S, N, or NH;wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², R³, R⁴, or R⁵; R¹¹ is R² or Y; R²²is R¹, R², or R⁴; R¹ is oxo, ═NN(R⁶)₂, ═NN(R⁷)₂, ═NN(R⁶R⁷), ═N—OR⁶,═N—OR⁷, R⁶ or (CH₂)_(n)—Y; or two R¹ on adjacent ring atoms, takentogether, form 1,2-methylenedioxy or 1,2-ethylenedioxy; n is 0, 1 or 2;Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶,N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶; R² is hydrogen or C1-C6 aliphatic,wherein each R² is optionally substituted with up to 2 substituentsindependently selected from R¹, R⁴, or R⁵; R³ is a C3-C8 cycloaliphatic,C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, wherein eachR³ is optionally substituted with up to 3 substituents independentlyselected from R¹, R², R⁴ or R⁵; R⁴ is OR^(S), OR⁶, OC(O)R⁶, OC(O)R⁵,OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂, OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂,OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵), SR⁶, SR^(S), S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵,SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶, SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶,C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂, C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶,C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵, C(NOR⁶)R⁶, C(NOR⁶)R⁵,C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶), NR⁵C(O)R⁵, NR⁶C(O)R⁶,NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵, NR⁵C(O)OR⁵,NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂, NR⁵C(O)NR⁵R⁶,NR⁵C(O)N(R⁵)₂, NR⁶C(S)N(R⁶)₂, NR⁶C(S)NR⁵R⁶, NR⁶C(S)N(R⁵)₂,NR⁵C(S)N(R⁶)₂, NR⁵C(S)NR⁵R⁶, NR⁵C(S)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵,NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶,NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂,P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂,P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶)(OR⁵); R⁵ is aC3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10heteroaryl ring, wherein each R⁵ optionally substituted with up to 3 R¹substituents; R⁶ is H or C1-C6 aliphatic, wherein R⁶ is optionallysubstituted with a R⁷ substituent; R⁷ is a C3-C8 cycloaliphatic, C6-C10aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, and each R⁷ isoptionally substituted with up to 2 substituents independently selectedfrom C1-C6 aliphatic, or (CH₂)_(m)—Z′ wherein m is 0-2; Z′ is selectedfrom halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo), —OC(halo)₃,—OCH(halo)₂, —OCH₂(halo), OH, S—(C1-C6) aliphatic, S(O)—(C1-C6)aliphatic, SO₂—(C1-C6)aliphatic, NH₂, NH—(C1-C6)aliphatic,N((C1-C6)aliphatic)₂, N((C1-C6)aliphatic)R⁸, COOH,C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic; and R⁸ is CH₃C(O)—,C6-C10 aryl sulfonyl-, or C1-C6 alkyl sulfonyl-.
 2. The method accordingto claim 1, wherein said method is used for treating or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain.
 3. Themethod according to claim 1, wherein said method is used for treating orlessening the severity of radicular pain, back pain, head pain, neckpain, intractable pain, acute pain, postsurgical pain, back pain, orcancer pain.
 4. The method according to claim 1, wherein w is
 0. 5. Themethod according to claim 1, wherein Z is selected from:

wherein Z has up to two R^(Z) substituents independently selected fromR′, R², or R⁵.
 6. The method according to claim 5, wherein Z is anoptionally substituted ring having formula i or formula ii.
 7. Themethod according to claim 1, wherein X is selected from a bond,—C(R²)₂—, or —NR²—.
 8. The method according to claim 7, wherein X is—CH₂—, —CHMe-, —C(Me)₂- or —NH—.
 9. The method according to claim 1,wherein Q is selected from a bond, —O—, —S—, —NR²—, —NH— or —N(C1-C6)alkyl-.
 10. The method according to claim 1, wherein Q is a C1-C6straight or branched alkylidene chain, wherein up to one methylene unitof Q is replaced by 0, S, NH, N(C1-C4 alkyl), or a spirocycloalkylenegroup.
 11. The method according to claim 1, wherein R^(Q) is a phenyloptionally substituted with up to 4 substituents independently selectedfrom R¹, R², R³, R⁴, or R⁵.
 12. The method according to claim 11,wherein R^(Q) is a phenyl ring optionally substituted with up to 3substituents independently selected from halo, CN, CF₃, OH, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₁₋₄ alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, NHC(O)C₁₋₄ alkyl, or C(O)C₁₋₄ alkyl.
 13. Themethod according to claim 1, wherein R^(Q) is an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from O, S, N, orNH, wherein R^(Q) is optionally substituted with up to 4 substituentsindependently selected from R¹, R², R³, R⁴, or R⁵.
 14. The methodaccording to claim 13, wherein R^(Q) is an optionally substituted ringselected from:


15. The method according to claim 1, wherein said compound has formulaIIA:

wherein U and T each is independently CH or N; provided that both U andT are not simultaneously N; R²² is R¹ or R²; R^(Z) is selected from R¹,R², or R⁵; z is 0-4; q is 0-2; v is 0 or 1; Q is C1-C4 alkylidene,wherein up to two non-adjacent methylene units of Q are optionally andindependently replaced by —CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—,—CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—,—NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—, —NR²SO₂NR²—, or aspirocycloalkylene moiety; and R^(Q) is a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from O, S, N, or NH, or an 8-15membered saturated, partially unsaturated, or fully unsaturated bicyclicring or tricyclic fused or spirocyclic ring system having 0-5heteroatoms independently selected from O, S, N, or NH; wherein R^(Q) isoptionally substituted with up to 4 substituents independently selectedfrom R¹, R², R³, R⁴, or R⁵.
 16. The method according to claim 15,wherein each of v, q, and z is zero.
 17. The method according to claim15, wherein U is N and T is CH.
 18. The method according to claim 15,wherein U is CH and T is N.
 19. The method according to claim 15,wherein U and T, both are CH.
 20. The method according to claim 15,wherein Q is C1-C4 straight or branched alkylidene.
 21. The methodaccording to claim 20, wherein Q is —CH₂—, —CH₂—CH₂—, —CH(Me)—,—C(Me)₂-, —CH(i-Pr)—.
 22. The method according to claim 1, wherein saidcompound has formula IVA:

wherein U and T each is independently CH or N; provided that both U andT are not simultaneously N; R²² is R¹ or R²; R^(Z) is selected from R¹,R², or R⁵; z is 0-4; q is 0-2; v is 0 or 1; Q is C1-C4 alkylidene,wherein up to two non-adjacent methylene units of Q are optionally andindependently replaced by —CO—, —CS—, —COCO—, —CONR²—, —CONR²NR²—,—CO₂—, —OCO—, —NR²CO₂—, —O—, —NR²CONR²—, —OCONR²—, —NR²NR², —NR²NR²CO—,—NR²CO—, —S—, —SO, —SO₂—, —NR²—, —SO₂NR²—, NR²SO₂—, —NR²SO₂NR²—, or aspirocycloalkylene moiety; and R^(Q) is a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from O, S, N, or NH, or an 8-15membered saturated, partially unsaturated, or fully unsaturated bicyclicring or tricyclic fused or spirocyclic ring system having 0-5heteroatoms independently selected from O, S, N, or NH; wherein R^(Q) isoptionally substituted with up to 4 substituents independently selectedfrom R¹, R², R³, R⁴, or R⁵.
 23. The method according to claim 22,wherein each of v, q, and z is zero.
 24. The method according to claim22, wherein U is N and T is CH.
 25. The method according to claim 22,wherein T is N and U is CH.
 26. The method according to claim 22,wherein U and T, both are CH.
 27. The method according to claim 22,wherein Q is C1-C4 straight or branched alkylidene.
 28. The methodaccording to claim 27, wherein Q is —CH₂—, —CH₂—CH₂—, —CH(Me)—,—C(Me)₂-, or —CH(i-Pr)—.
 29. The method according to claim 1, whereinsaid compound is selected from the following: